Thiazoline derivatives

ABSTRACT

Object: To provide compounds useful as inhibitors of blood platelet aggregation for intravenous administration. 
     Constitution: A thiazoline derivative represented by the formula: ##STR1##  wherein R 1  is a hydroxyl group, an alkoxy group, a cycloalkoxy group or a group represented by the formula: R 4  NH-- (wherein R 4  is a cycloalkyl group), R 2  is an alkyl group, a cycloalkyl group or a phenylalkyl group, R 3  is a hydrogen atom or an alkyl group, and n is an integer of 2 to 9! or a salt thereof.

This application is a 371 of PCT/JP95/01169 filed Jun. 12, 1995.

TECHNICAL FIELD

The present invention relates to novel thiazoline derivatives having aninhibitory action of blood platelet aggregation.

BACKGROUND ART

Blood platelet aggregation is considered to occur by the appearance ofthe binding site to the fibrinogen on the blood platelet membraneglycoprotein GPIIb/IIIa complex caused by stimulation of various bloodplatelet aggregation-inducing substances. Accordingly, the compoundshaving an antagonism to fibrinogen receptors have a possibility to showan inhibitory action of blood platelet aggregation.

Compounds disclosed in WO 94/02472 are thiazoline derivatives having anantagonism of fibrinogen receptors, thereby having an inhibitory actionof blood platelet aggregation.

However, the compounds disclosed in WO 94/02472 are lowly water-solubleand have a problem of stability in an aqueous solution. Therefore, whenadministered in the form of an injection solution, these compounds areinsufficient for utility as medicines.

An object of the present invention is to provide compounds having anexcellent inhibitory action of blood platelet aggregation and goodsolubility in water, i.e. compounds practicable as an inhibitor of bloodplatelet aggregation for intravenous administration.

DISCLOSURE OF THE INVENTION

As a result of extensive researches, the present inventors have foundthat certain thiazoline derivatives achieve the above-mentioned object,and thereby the present invention has been accomplished.

The present invention is a thiazoline derivative represented by Formula:##STR2## wherein R¹ is a hydroxyl group, an alkoxy group having 1 to 6carbon atoms, a cycloalkoxy group having 3 to 6 carbon atoms or a grouprepresented by the formula:

    R.sup.4 NH--

(wherein R⁴ is a cycloalkyl group having 3 to 6 carbon atoms or a phenylgroup), R² is an alkyl group having 1 to 14 carbon atoms, a cycloalkylgroup having 3 to 6 carbon atoms or a phenylalkyl group having 7 to 10carbon atoms, R³ is a hydrogen atom or an alkyl group having 1 to 6carbon atoms, and n is an integer of 2 to 9! or a pharmaceuticallyacceptable salt thereof.

In the present invention, the alkyl group as used by itself or as a partof certain group refers to a straight or branched alkyl group, i.e.,examples of the alkyl group having 1 to 6 carbon atoms are a methylgroup, an ethyl group, a propyl group, an isopropyl group, a butylgroup, an isobutyl group, a tert-butyl group, a pentyl group, anisopentyl group and a hexyl group, and examples of the alkyl grouphaving 1 to 14 carbon atoms are, besides the group given above, a2-methylhexyl group, a 3-methylhexyl group, a heptyl group, an octylgroup, a decyl group and a tetradecyl group. In addition, the cycloalkylgroup having 3 to 6 carbon atoms refers to a cyclopropyl group, acyclobutyl group, a cyclopentyl group and a cyclohexyl group. Examplesof the phenylalkyl group having 7 to 10 carbon atoms are a benzyl group,a phenethyl group and a phenylpropyl group.

The pharmaceutically acceptable salt of the compound of Formula (I)refers to, for example, salts with an alkali metal, an alkali earthmetal, ammonia, an alkylamine, a mineral acid, a carboxylic acid or asulfonic acid, and more especially sodium salt, potassium salt, calciumsalt, ammonium salt, aluminium salt, triethylammonium salt,hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate,monomethylsulfate, acetate, propionate, butyrate, succinate, tartrate,citrate, tannate, malate, caproate, valerate, fumarate, maleate,methanesulfonate, tosylate or trifluoroacetate.

Preferred compounds of the present invention are those wherein R³ is ahydrogen atom, especially those wherein R¹ is a hydroxyl group and R³ isa hydrogen atom, and more especially those wherein R¹ is a hydroxylgroup, R³ is a hydrogen atom and R² is a methyl group.

The most preferred compounds of the present invention areN-(2-carboxyethyl)-2-{4-N-(3-carboxypropyl)amidino!benzoylimino}-3,4-dimethyl-3H-thiazoline-5-carboxamideand N-(2-carboxyethyl)-2-{4-N-(2-carboxyethyl)amidino!benzoylimino}-3,4-dimethyl-3H-thiazoline-5-carboxamide.

The compounds of the present invention can be prepared by the followingmethods.

For the preparation of the compounds of the present invention, first, acompound represented by the following Formula (a): ##STR3## (wherein R⁵is an alkyl group having 1 to 6 carbon atoms), which can be obtained byreacting 4-cyanobenzoyl chloride with a4-methyl-2-aminothiazole-5-carboxylate, is reacted with an alkylatingagent such as, for example, a halide represented by the formula:

    R.sup.2 --X

(wherein X is a halogen atom and R² is as defined above), a compoundrepresented by the formula:

    R.sup.2.sub.2 --SO.sub.4

(wherein R² is as defined above) or a sulfonate (e.g. methylmethanesulfonate) represented by the formula:

    R.sup.6 --SO.sub.3 --R.sup.2

(wherein R⁶ is an alkyl group or an aryl group, and R² is as definedabove) in the presence of a base to give a compound represented byFormula (b): ##STR4## (wherein R² and R⁵ are as defined above).

Alternatively, the compound of Formula (b) may be also prepared by thefollowing method.

A compound represented by the following Formula (c): ##STR5## (whereinR² is as defined above) which can be prepared, for example, by themethod described in Org. Synth. Coll., vol. 3, page 735, is reacted witha compound represented by the formula:

    CH.sub.3 COCH(X)CO.sub.2 R.sup.5

(wherein X is a halogen atom and R⁵ is as defined above) in the presenceor absence of a base in a solvent or without solvent under heating togive a compound of Formula (b).

Next, the ester moiety of the compound of Formula (b) is hydrolyzedaccording to a conventional method to lead to a compound represented byFormula (d): ##STR6## (wherein R² is as defined above) or a saltthereof, and the resulting compound is amidated using a compoundrepresented by the formula:

    H.sub.2 N--(CH.sub.2).sub.2 --CO.sub.2 R.sup.7

(wherein R⁷ is R³ other than a hydrogen atom) or a salt thereofaccording to a conventional method for formation of amide linkage togive a compound represented by Formula (e): ##STR7## (wherein R² and R⁷are as defined above). The compound of Formula (e) is subjected, forexample, to a reaction with hydrogen sulfide by using a base as acatalyst, or a reaction with NaBH₂ S₃ to lead to a compound representedby Formula (f): ##STR8## (wherein R² and R⁷ are as defined above), whichis then treated with a lower alkyl halide represented by the formula:

    R.sup.8 --X

(wherein R⁸ is an alkyl group having 1 to 6 carbon atoms, and X is ahalogen atom) or a compound of the formula:

    R.sup.8.sub.2 --SO.sub.4

(wherein R⁸ is as defined above) to lead to a compound represented byFormula (g): ##STR9## (wherein R², R⁷ and R⁸ are as defined above) or asalt thereof. This compound is treated with a compound represented byFormula (h):

    R.sup.1 OC(CH.sub.2).sub.n NH.sub.2                        (h)

(wherein R¹ and n are as defined above) or a salt thereof in thepresence or absence of an acid or a base to lead to a compound of thepresent invention wherein R³ is an alkyl group having 1 to 6 carbonatoms.

The compound of the present invention wherein R³ is a hydrogen atom or asalt thereof can be also prepared by hydrolysis of the ester moiety ofthe compound of the present invention wherein R³ is an alkyl grouphaving 1 to 6 carbon atoms. The hydrolysis of the ester to be used is anordinary method such as treatments with an alkali, a mineral acid or anorganic acid. The compounds of the present invention wherein R³ is analkyl group having 1 to 6 carbon atoms can be also converted each otherby transesterification using an acid as a catalyst.

Examples of the base to be used in the above-mentioned reaction are analkali metal salt (e.g. sodium carbonate, potassium carbonate, sodiumbicarbonate, potassium bicarbonate, sodium hydroxide, potassiumhydroxide, dimsyl sodium, sodium hydride, sodium amide or potassiumtert-butyl), an amine (e.g. triethylamine, diisopropylethylamine orpyridine), sodium acetate and potassium acetate; examples of the mineralacid are hydrochloric acid, hydrobromic acid, hydroiodic acid, nitricacid and sulfuric acid; and examples of the organic acid are aceticacid, methanesulfonic acid and p-toluenesulfonic acid.

Examples of the reaction solvent to be used are reaction-inert solventssuch as water, an alcohol (e.g. methanol, ethanol, isopropyl alcohol ortert-butyl alcohol), an ether (e.g. dioxane or tetrahydrofuran),dimethylformamide, dimethyl sulfoxide, pyridine, methylene chloride,chloroform, acetone and acetic acid.

INDUSTRIAL UTILIZABILITY

The thus-obtained compounds of Formula (I) inhibit the binding ofvarious adhesive proteins such as fibrinogen, fibronectin and vonWillebrand factor against fibrinogen receptor (GpIIb/IIIa) on bloodplatelet, and have the inhibitory action of the aggregation and adhesionof blood platelet.

Accordingly, the compounds of the present invention can be used aspreventive and therapeutic agents of ischemic diseases (e.g. thrombosis,cerebral infarction or myocardial infarction) and arteriosclerosisdiseases.

For the purposes, the compounds of Formula (I) can be mixed with, forexample, conventional fillers, pH modulators or solubilizers, andprepared in the form of injection solutions by conventional formulationtechniques.

The dose of the compound of Formula (I) for adult patients is 0.01 to100 mg per day, which can be given in a single dose or in severaldivided doses. This dose can be increased or decreased depending on thekind of the diseases and the age, body weight and condition of thepatient.

Fibrinogen receptor antagonism of the compounds of Formula (I) isillustrated by the following experiments.

Experiment 1 Human Blood Platelet Fibrinogen Binding Test!

The test was carried out referring to the methods of G. A. Marguerie (J.Biol. Chem., vol. 254, pages. 5357-5363, 1979) and N. S. Nicholson(Thromb. Res., vol. 50, pages 567-578, 1991).

Citrated blood (the volume ratio of 3.13% sodium citrate solution andblood is 1:9) was collected from the cubital vein of a healthy human whohad not received any drugs known to affect the function of bloodplatelet within 2 weeks prior to starting the test, and centrifuged at120× g at room temperature for 15 minutes to give platelet rich plasma(PRP) as a supernatant.

To the above PRP was added one fifth volume of an ACD solution (citricacid/sodium citrate/dextrose), followed by centrifugation at 1200× g for15 minutes. The precipitate was suspended in a Tyrode's solution (20%fetal bovine serum, 2 mM Mg²⁺), followed by gel filtration usingSepharose 2B column to give a fibrinogen-free blood platelet suspension(1×10⁹ /ml). The binding test was carried out by using thefibrinogen-free blood platelet suspension, the solutions of thecompounds of Formula (I) in dimethyl sulfoxide which were each adjustedto the desired concentration by diluting with a physiological salinesolution as test drugs, ADP (final concentration: 10 μM) and ¹²⁵ Ilabeled human fibrinogen, and then the binding inhibitory rate of thetest drug was calculated.

N-(2-Carboxyethyl)-2-(4-amidinobenzoylimino)-3,4-dimethyl-3H-thiazoline-5-carboxamidehydrobromide (described in WO 94/02472; referred to as "Comparativedrug" in the following experiments) was used as a comparative drug. Thedrug solution was prepared in the same manner as described above, andtested as described above.

The results are shown in Table 1 in which the compound numbers are thesame as defined in the following examples and are also used in thefollowing experiments.

                  TABLE 1                                                         ______________________________________                                        Test drug      IC.sub.50 value (nM)                                           ______________________________________                                        Compound 8     25.6                                                           Compound 9     16.5                                                           Compound 11    8.2                                                            Compound 12    4.7                                                            Compound 17    12.6                                                           Compound 49    7.2                                                            Compound 51    8.6                                                            Compound 56    11.1                                                           Comparative drug                                                                             5.0                                                            ______________________________________                                    

Experiment 2 Human in vitro Blood Platelet Aggregation Inhibition Test!

Citrated blood (the volume ratio of 3.13% sodium citrate solution andblood is 1:9) was collected from the cubital vein of a healthy human whohad not received any drugs known to affect the function of bloodplatelet within 2 weeks prior to starting the test, and centrifuged at120× g at room temperature for 15 minutes to give platelet rich plasma(PRP) as a supernatant. The remaining precipitate was furthercentrifuged at 1500× g for 10 minutes to give platelet poor plasma (PPP)as a supernatant. The blood platelet counts of PRP were adjusted to50˜60×10⁴ /μl by diluting with PPP.

Blood platelet aggregation was monitored according to the method of BornG. V. R., Nature, vol. 194, page 927 (1962)! using adenosine diphosphate(produced by Sigma Co.; hereinafter referred to as "ADP") as anaggregation-inducing substance. That is, a solution of the compound ofFormula (I) as a test drug in dimethyl sulfoxide was adjusted to thedesired concentration with a physiological saline solution. 25 μl of thesolution was added to 250 μl of PRP and incubated at 37° C. for 3minutes, and 25 μl of ADP (final concentration: 7 μM) was added thereto.The mixture was measured for 5 minutes by using a blood plateletaggregation ability measurement apparatus (Aggricoda TM•PA-3210; made byKyoto Daiichi Kagaku Co.) to give the maximum aggregation, and theconcentration of the test drug to bring 50% inhibition of the maximumaggregation (IC₅₀) was calculated.

Results are shown in Table 2.

                  TABLE 2                                                         ______________________________________                                        Test drug      IC.sub.50 value (nM)                                           ______________________________________                                        Compound 8     39                                                             Comparative drug                                                                             17                                                             ______________________________________                                    

Experiment 3 Solubility Test!

Solubility test was carried out referring to the method of S. Miyazakiet al. Chem. Pharm. Bull., vol. 23, page 1197 (1975)!.

9.511 g of disodium hydrogenphosphate weighed accurately was dissolvedin 800 ml of water. The solution was adjusted to pH 7.0 by adding sodiumdihydrogenphosphate, and the total volume of the solution was madeexactly 1000 ml to give a 0.1M phosphate buffer (pH 7). To 1.0 ml of thebuffer solution measured exactly was added an excess amount for thesolubility limit of the test drug. The suspension was treated bysupersonic waves for 5 minutes and stirred on a water bath at 25° C. for24 hours. After removal of the insoluble substance by using a membranefilter (0.22 μm), the filtrate was appropriately diluted to give a testsolution. Separately, 1 mg of the test drug weighed accurately wasdissolved in the eluate to make exactly 100 ml to give a standardsolution. The test solution and the standard solution were quantified byhigh performance liquid chromatography method under the followingprocedure conditions, and the solubility of the test drug wascalculated.

The results are shown in Table 3.

Procedure Conditions:

Detection instrument: Ultraviolet spectrophotometer (Detection wavelength: 246 nm)

Column: ODS column 4.6φ×150 mm (TSK Gel ODS 80TM)

Column temperature: A definite temperature in the vicinity of 50° C.

Mobile phase: Water:acetonitrile:sodium dodecylsulfate:phosphoricacid=400:600:3:1

Flow rate: 1.0 ml/min.

Injection amount: 10 μl

                  TABLE 3                                                         ______________________________________                                        Test drug      Solubility (mg/ml                                              ______________________________________                                        Compound 8     20                                                             Comparative drug                                                                             0.03                                                           ______________________________________                                    

Experiment 4 Stability Test!

Stability test was carried out referring to the method of A. K.Amirjahed et al J. Pharm. Sci., vol. 66, page 785 (1977)!.

20 mg of Compound 8 obtained in the following example and 20 mg ofComparative drug, each weighed accurately, were each dissolved in 0.1Nphosphate buffer (a buffer of a suitable amount of 0.1M potassiumdihydrogenphosphate mixed with a suitable amount of 0.1M disodiumhydrogenphosphate to adjust to pH 7) to make exactly 1000 ml to givestandard solutions, respectively. The solution was dispensed intoampules, and they were stored at 80° C. for 4 hours, 8 hours and 24hours to prepare test solutions.

20 μl of the test solution and 20 μl of the standard solution were eachquantified by high performance liquid chromatography method under thefollowing procedure conditions, and the peak areas of Compound 8 andComparative drug at the storage times were determined, and the remainingrate was calculated by using the following formula, and the results areshown in Table 4.

Detection instrument: Ultraviolet spectrophotometer (Detection wavelength: 247 nm)

Column: ODS column 4.6φ×150 mm (TSK Gel ODS 80TM)

Column temperature: A definite temperature in the vicinity of 50° C.

Mobile phase:

Compound 8! 1 ml of phosphoric acid and 5 g of sodium dodecylsulfate(SDS) are added to 1000 ml of a mixture of water and acetonitrile(65:35).

Comparative drug! 1 ml of phosphoric acid and 3 g of sodiumdodecylsulfate (SDS) are added to 1000 ml of a mixture of water andacetonitrile (60:40).

Flow rate: 1 ml/min.

Formula: Remaining rate (%)= ##EQU1##

                  TABLE 4                                                         ______________________________________                                                     Remaining rate (%) of Test drug                                  Storage time   Compound 8                                                                              Comparative drug                                     ______________________________________                                        Immediately after                                                                            100       100                                                  After 4 hours  97.8      82.2                                                 After 8 hours  95.7      68.4                                                 After 24 hours 88.9      32.3                                                 ______________________________________                                    

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is illustrated in more detail by the followingexamples. The structures of the compounds obtained in Examples are shownin the following Table 5.

                  TABLE 5                                                         ______________________________________                                         ##STR10##                                                                    Compound No.                                                                           R.sup.1  n      R.sup.2 R.sup.3                                                                             Salt                                   ______________________________________                                         1       OH       3      Me      Me    HI                                      2       OH       2      Me      Me    HI                                      3       OH       5      Me      Me    HI                                      4       OMe      3      Me      Me    MeOSO.sub.3 H                           5       OMe      2      Me      Me    MeOSO.sub.3 H                           6       O-c.Hex  3      Me      Me    MeOSO.sub.3 H                           7       NH-c.Hex 3      Me      Me    MeOSO.sub.3 H                           8       OH       3      Me      H                                             9       OH       2      Me      H                                            10       OH       5      Me      H                                            11       O-c.Hex  3      Me      H                                            12       NH-c.Hex 3      Me      H                                            13       O-c.Hex  3      i-Pr    Me    MeOSO.sub.3 H                          14       OMe      3      i-Pr    Me    HI                                     15       OH       3      i-Pr    Me    MeOSO.sub.3 H                          16       OH       3      i-Pr    H                                            17       O-c.Hex  3      i-Pr    H                                            18       O-c.Hex  3      n-Bu    Me    MeOSO.sub.3 H                          19       O-c.Hex  3      n-Bu    H                                            20       OH       3      n-Bu    H                                            21       OH       3      C.sub.6 H.sub.13                                                                      t-Bu                                         22       OMe      3      C.sub.6 H.sub.13                                                                      t-Bu                                         23       O-c.Hex  3      C.sub.6 H.sub.13                                                                      t-Bu                                         24       OH       3      C.sub.6 H.sub.13                                                                      H     CF.sub.3 CO.sub.2 H                    25       OMe      3      C.sub.6 H.sub.13                                                                      H     CF.sub.3 CO.sub.2 H                    26       O-C.Hex  3      C.sub.6 H.sub.13                                                                      H     CF.sub.3 CO.sub.2 H                    27       OH       3      H.sub.14 H.sub.29                                                                     t-Bu                                         28       OMe      3      H.sub.14 H.sub.29                                                                     t-Bu                                         29       O-c.Hex  3      H.sub.14 H.sub.29                                                                     t-Bu                                         30       OH       3      H.sub.14 H.sub.29                                                                     H     CF.sub.3 CO.sub.2 H                    31       OMe      3      H.sub.14 H.sub.29                                                                     H     CF.sub.3 CO.sub.2 H                    32       O-c.Hex  3      H.sub.14 H.sub.29                                                                     H     CF.sub.3 CO.sub.2 H                    33       OMe      3      Bn      Me    MeOSO.sub.3 H                          34       O-c.Hex  3      Bn      Me    MeOSO.sub.3 H                          35       OH       3      Bn      H                                            36       O-c.Hex  3      Bn      H                                            37       OH       3      Ph(CH.sub.2).sub.2                                                                    t-Bu                                         38       OMe      3      Ph(CH.sub.2).sub.2                                                                    t-Bu                                         39       O-c.Hex  3      Ph(CH.sub.2).sub.2                                                                    t-Bu                                         40       OH       3      Ph(CH.sub.2).sub.2                                                                    H     CF.sub.3 CO.sub.2 H                    41       OMe      3      Ph(CH.sub.2).sub.2                                                                    H     CF.sub.3 CO.sub.2 H                    42       O-c.Hex  3      Ph(CH.sub.2).sub.2                                                                    H     CF.sub.3 CO.sub.2 H                    43       OMe      3      c.Pr    Me                                           44       O-c.Hex  3      c.Pr    Me    MeOSO.sub.3 H                          45       NH-c.Hex 3      c.Pr    Me    MeOSO.sub.3 H                          46       NHPh     5      c.Pr    Me    MeOSO.sub.3 H                          47       OH       3      c.Pr    Me    MeOSO.sub.3 H                          48       OH       3      c.Pr    H                                            49       O-c.Hex  3      c.Pr    H                                            50       NH-c.Hex 3      c.Pr    H                                            51       NHPh     5      c.Pr    H                                            52       OMe      3      c.Bu    Me                                           53       O-c.Hex  3      c.Bu    Me    MeOSO.sub.3 H                          54       OH       3      c.Bu    Me    MeOSO.sub.3 H                          55       OH       3      c.Bu    H                                            56       O-c.Hex  3      c.Bu    H                                            57       OMe      3      c.Pn    Me                                           58       O-c.Hex  3      c.Pn    Me    MeOSO.sub.3 H                          59       OH       3      c.Pn    Me    MeOSO.sub.3 H                          60       OH       3      c.Pn    H                                            61       O-c.Hex  3      c.Pn    H                                            62       OH       2      c.Hex   Me    HI                                     63       OH       3      c.Hex   Me    HI                                     64       OH       5      c.Hex   Me    HI                                     65       OH       2      c.Hex   H                                            66       OH       3      c.Hex   H                                            67       OH       5      c.Hex   H                                            ______________________________________                                         In Table 5, "c.Pr" is a cyclopropyl group, "c.Bu" is a cyclobutyl group,      "c.Pn" is a cyclopentyl group, "c.Hex" is a cyclohexyl group and "Bn" is      benzyl group.                                                            

EXAMPLE 1

(1) Ethyl 2-(4-cyanobenzoylamino)-4-methylthiazole-5-carboxylate (22.07g) was added to a suspension of 60% oily sodium hydride (3.08 g) inN,N-dimethylformamide (hereinafter referred to as DMF) (300 ml) underice-cooling, followed by stirring at room temperature for an hour. Asolution of methyl iodide (4.8 ml) in DMF (50 ml) was added dropwise tothe reaction mixture, followed by further stirring at room temperaturefor an hour. The reaction mixture was taken up in 3% hydrochloric acid,and the precipitated crystals were collected by filtration, and theresulting crude crystals were recrystallized from a mixture of methylenechloride and methanol to give ethyl2-(4-cyanobenzoylimino)-3,4-dimethylthiazoline-5-carboxylate (15.97 g).

m.p. 244°˜245° C.

(2) 10% Aqueous sodium hydroxide solution (48 ml) was added to a mixtureof ethyl 2-(4-cyanobenzoylimino)-3,4-dimethylthiazoline-5-carboxylate(9.88 g), methylene chloride (250 ml) and methanol (250 ml), followed bystirring at room temperature for 17 hours. The reaction mixture wasconcentrated under reduced pressure, and the precipitated crystals werecollected by filtration to give sodium2-(4-cyanobenzoylimino)-3,4-dimethylthiazoline-5-carboxylate (10.0 g).

¹ H-NMR (DMSO-d₆) δ (ppm); 2.66 (3H, s), 3.75 (3H, s), 7.91 (2H, d,J=8Hz), 8.33 (2H, d, J=8Hz).

(3) β-Alanine methyl ester hydrochloride (4.68 g),1-hydroxybenzotriazole monohydrate (hereinafter referred to as "HOBt.H₂O") (9.34 g) and 1-ethyl-3-{3-(dimethylamino)propyl}carbodiimidehydrochloride (hereinafter referred to as "WSC.HCl") (6.43 g) weresuccessively added to a of suspension of sodium2-(4-cyanobenzoylimino)-3,4-dimethylthiazoline-5-carboxylate (9.85 g) inDMF with stirring, followed by stirring at room temperature for 14hours. The reaction mixture was taken up in water, and the precipitatedcrystals were collected by filtration and recrystallized from a mixtureof methylene chloride and hexane to giveN-(2-methoxycarbonylethyl)-2-(4-cyanobenzoylimino)-3,4-dimethyl-3H-thiazoline-5-carboxamide(9.9 g).

m.p. 187.5°˜189.5° C.

(4) A mixture ofN-(2-methoxycarbonylethyl)-2-(4-cyanobenzoylimino)-3,4-dimethyl-3H-thiazoline-5-carboxamide(9.66 g), sodium hydrosulfide (70%, 3.7 g), magnesium chloridehexahydrate (4.7 g) and DMF (175 ml) was stirred at room temperature foran hour. After addition of water (700 ml), the precipitated crystalswere collected by filtration, and the resulting crude crystals werewashed with 3% hydrochloric acid to giveN-(2-methoxycarbonylethyl)-2-(4-thiocarbamoylbenzoylimino)-3,4-dimethyl-3H-thiazoline-5-carboxamide(10.56 g).

m.p. 215.5°˜216.5° C.

(5) Methyl iodide (28 ml) was added in 4-portions at 30 minute intervalsto a suspension ofN-(2-methoxycarbonylethyl)-2-(4-thiocarbamoylbenzoylimino)-3,4-dimethyl-3H-thiazoline-5-carboxamide(6.31 g) in acetone (1600 ml) under heating reflux, followed by stirringfor 4 hours. The reaction mixture was concentrated under reducedpressure, and the precipitated crystals were collected by filtration togive N-(2-methoxycarbonylethyl)-2-4-(methylthioimidoyl)benzoylimino!-3,4-dimethyl-3H-thiazoline-5-carboxamidehydroiodide (7.69 g).

m.p. 203.5°˜204° C.

(6) A mixture ofN-(2-methoxycarbonylethyl)-2-(4-thiocarbamoylbenzoylimino)-3,4-dimethyl-3H-thiazoline-5-carboxamideobtained in (4) (104 g), DMF (400 ml) and dimethyl sulfate (86.1 ml) wasstirred at room temperature for 4 hours. Acetone (1.5 l) was added, andthe resulting crystals were collected by filtration and washed withacetone to give N-(2-methoxycarbonylethyl)-2-4-(methylthioimidoyl)benzoylimino!-3,4-dimethyl-3H-thiazoline-5-carboxamidemethylsulfate (126.45 g).

m.p. 164°-167° C.

(7) N-(2-Methoxycarbonylethyl)-2-4-(methylthioimidoyl)benzoylimino!-3,4-dimethylthiazoline-5-carboxamidehydroiodide (2.0 g) was added to a mixture of 4-aminobutyric acid (0.37g), acetic acid (0.2 ml) and methanol (20 ml) under heating reflux, andthe mixture was further heated under reflux for an hour. The reactionmixture was concentrated, and the precipitated crystals were collectedby filtration to give N-(2-methoxycarbonylethyl)-2-{4-N-(3-carboxypropyl)amidino!benzoylimino}-3,4-dimethyl-3H-thiazoline-5-carboxamidehydroiodide (Compound 1).

m.p. 204°˜210° C.

Following the reaction procedure similar to that of Example 1, thefollowing compounds were obtained.

N-(2-Methoxycarbonylethyl)-2-{4-N-(2-carboxyethyl)amidino!benzoylimino}-3,4-dimethyl-3H-thiazoline-5-carboxamidehydroiodide (Compound 2)

m.p. 175°˜177° C.

N-(2-Methoxycarbonylethyl)-2-{4-N-(5-carboxypentyl)amidino!benzoylimino}-3,4-dimethyl-3H-thiazoline-5-carboxamidehydroiodide (Compound 3)

m.p. 210°˜213° C.

EXAMPLE 2

N-(2-Methoxycarbonylethyl)-2-4-(methylthioimidoyl)benzoylimino!-3,4-dimethylthiazoline-5-carboxamidemethylsulfate (10.0 g) obtained in Example 1(6) was added to a mixtureof methyl 4-aminobutyrate hydrochloride (2.81 g), sodium acetate (1.5 g)and methanol (100 ml) under heating reflux, and the reaction mixture wasfurther heated under reflux for an hour. The reaction mixture wasconcentrated and the resulting crystals were collected by filtration togive N-(2-methoxycarbonylethyl)-2-{4-N-(3-methoxycarbonylpropyl)amidino!benzoylimino}-3,4-dimethyl-3H-thiazoline-5-carboxamidemethylsulfate (Compound 4).

m.p. 209.5°˜210° C.

Following the reaction procedure similar to that of Example 2, thefollowing compound was obtained.

N-(2-Methoxycarbonylethyl)-2-{4-N-(2-methoxycarbonylethyl)amidino!benzoylimino}-3,4-dimethyl-3H-thiazoline-5-carboxamidemethylsulfate (Compound 5).

m.p. 196°˜198.5° C.

EXAMPLE 3

N-(2-Methoxycarbonylethyl)-2-4-(methylthioimidoyl)benzoylimino!-3,4-dimethyl-3H-thiazoline-5-carboxamidemethylsulfate (2.0 g) obtained in Example 1(6) was added to a mixture ofcyclohexyl 4-aminobutyrate methanesulfonate (1.63 g), sodium acetate(0.45 g) and methanol (20 ml) under heating reflux, and the reactionmixture was further heated under reflux for an hour. To the reactionmixture was added acetone (40 ml), and the precipitated crystals werecollected by filtration to give N-(2-methoxycarbonylethyl)-2-{4-N-(3-cyclohexyloxycarbonylpropyl)amidino!benzoylimino}-3,4-dimethyl-3H-thiazoline-5-carboxamidemethylsulfate (Compound 6).

m.p. 217°˜217.5° C.

EXAMPLE 4

Following the procedure similar to that of Example 3 using4-amino-N-cyclohexylbutyramide hydrochloride in place of cyclohexyl4-aminobutyrate methanesulfonate, N-(2-methoxycarbonylethyl)-2-{4-N-(3-cyclohexylaminocarbonylpropyl)amidino!benzoylimino}-3,4-dimethyl-3H-thiazoline-5-carboxamidemethylsulfate (Compound 7) was obtained.

m.p. 228°˜228.5° C.

EXAMPLE 5

10% Aqueous sodium hydroxide solution (210 ml) was added to a mixture ofCompound 4 (64.5 g), methanol (323 ml) and 2-propanol (323 ml), followedby stirring at room temperature for an hour. The reaction solution waspoured into 50% acetic acid (645 ml), and after ice-cooling, theprecipitated crystals were collected by filtration to giveN-(2-carboxyethyl)-2-{4-N-(3-carboxypropyl)amidino!benzoylimino}-3,4-dimethyl-3H-thiazoline-5-carboxamide(Compound 8).

m.p. 249.5°˜250° C.

EXAMPLE 6

A mixture of Compound 2 (0.25 g), 10% aqueous sodium hydroxide solution(0.84 ml) and methanol (5 ml) was stirred at room temperature for anhour, followed by evaporation under reduced pressure. The residue wasdissolved in water and acidified with 3% aqueous hydrochloric acidsolution, and the precipitated crystals were collected by filtration togive N-(2-carboxyethyl)-2-{4-N-(2-carboxyethyl)amidino!-benzoylimino}-3,4-dimethyl-3H-thiazoline-5-carboxamide(Compound 9).

m.p. 215°˜218° C. (decomposed)

Following the reaction procedure similar to that of Example 6, thefollowing compound was obtained.

N-(2-Carboxyethyl)-2-{4-N-(5-carboxypentyl)amidino!benzoylimino}-3,4-dimethyl-3H-thiazoline-5-carboxamide(Compound 10).

m.p. 230°˜231.5° C.

EXAMPLE 7

A mixture of Compound 6 (1.0 g), 10% aqueous sodium hydroxide solution(1.2 ml) and 2-propanol (10 ml) was stirred under ice-cooling for anhour. To the reaction mixture were added 10% aqueous sodium dihydrogenphosphate solution and water, and the precipitated crystals werecollected by filtration to give N-(2-carboxyethyl)-2-{4-N-(3-cyclohexyloxycarbonylpropyl)amidino!benzoylimino}-3,4-dimethyl-3H-thiazoline-5-carboxamide(Compound 11).

m.p. 203.5°˜204° C.

EXAMPLE 8

A mixture of Compound 7 (0.3 g), 10% sodium hydroxide solution (0.37 ml)and 2-propanol (3 ml) was stirred at room temperature for 30 minutes. Tothe reaction mixture was added acetic acid, and the precipitatedcrystals were collected by filtration to give N-(2-carboxyethyl)-2-{4-N-(3-cyclohexylaminocarbonylpropyl)amidino!benzoylimino}-3,4-dimethyl-3H-thiazoline-5-carboxamide(Compound 12).

m.p. 217.5°˜218° C.

EXAMPLE 9

(1) 4-Cyanobenzoyl chloride (10 g) was added in portions to a solutionof ammonium thiocyanate (4.6 g) in acetone (100 ml) at room temperature,followed by heating under reflux for 10 minutes. The reaction mixturewas ice-cooled, and after removal of the insoluble substance byfiltration, the filtrate was evaporated under reduced pressure to give4-cyanobenzoyl isothiocyanate (11.2 g).

m.p. 87.5°˜88.5° C.

(2) Isopropylamine (5.6 ml) was added dropwise to a mixture of4-cyanobenzoyl isothiocyanate (11 g) and toluene (100 ml) at 60° C., andthe insoluble substance in the reaction solution was filtered off. Afterallowing to stand for cooling, the precipitated crystals wererecrystallized from toluene to give1-(4-cyanobenzoyl)-3-isopropylthiourea (12.35 g) as pale yellow prisms.

m.p. 156°˜157° C.

(3) A mixture of 1-(4-cyanobenzoyl)-3-isopropylthiourea (37 g), ethyl2-chloroacetoacetate (59 g) and toluene (500 ml) was heated under refluxwith removing the water generated in the reaction for 3 hours. Thereaction mixture was allowed to stand for cooling, and then theprecipitated crystals were collected by filtration and recrystallizedfrom toluene to give ethyl2-(4-cyanobenzoylimino)-3-isopropyl-4-methyl-3H-thiazoline-5-carboxylate(45 g) as a pale yellow powder.

m.p. 207.5°˜209° C.

(4) A mixture of ethyl2-(4-cyanobenzoylimino)-3-isopropyl-4-methyl-3H-thiazoline-5-carboxylate(45.0 g), 10% aqueous sodium hydroxide solution (55.4 ml), dimethylsulfoxide (450 ml) and methylene chloride (450 ml) was stirred at roomtemperature for 2.5 hours. Methylene chloride and conc. hydrochloricacid were added to the reaction mixture, and then the methylene chloridewas evaporated. After addition of water, the precipitated crystals werecollected by filtration to give2-(4-cyanobenzoylimino)-3-isopropyl-4-methyl-3H-thiazoline-5-carboxylicacid (42.17 g).

m.p. 261°˜264° C. (decomposed)

(5) A mixture of2-(4-cyanobenzoylimino)-3-isopropyl-4-methyl-3H-thiazoline-5-carboxylicacid (10.0 g), 1,3-dimethyl-2-chloroimidazolium chloride (hereinafterreferred to as "DMC") (8.22 g) and β-alanine methyl ester hydrochloride(6.79 g), triethylamine (20.32 ml) and DMF (200 ml) was stirred at roomtemperature for 14 hours. The reaction solution was poured into water(800 ml), and the precipitated crystals were collected by filtration togiveN-(2-methoxycarbonylethyl)-2-(4-cyanobenzoylimino)-3-isopropyl-4-methyl-3H-thiazoline-5-carboxamide(11.67 g).

m.p. 139.5°˜140.5° C.

(6) A mixture ofN-(2-methoxycarbonylethyl)-2-(4-cyanobenzoylimino)-3-isopropyl-4-methyl-3H-thiazoline-5-carboxamide(11.0 g), sodium hydrosulfide (70%, 4.25 g), magnesium chloridehexahydrate (5.40 g) and DMF (200 ml) was stirred at room temperaturefor an hour. After addition of water (800 ml), the precipitated crystalswere collected by filtration, and the resulting crude crystals werewashed with 3% hydrochloric acid to giveN-(2-methoxycarbonylethyl)-2-(4-thiocarbamoylbenzoylimino)-3-isopropyl-4-methyl-3H-thiazoline-5-carboxamide(11.34 g).

m.p. 186°˜187° C.

(7) A mixture ofN-(2-methoxycarbonylethyl)-2-(4-thiocarbamoylbenzoylimino)-3-isopropyl-4-methyl-3H-thiazoline-5-carboxamide(11.0 g), DMF (35 ml) and dimethyl sulfate (10.5 ml) was stirred at roomtemperature for 2.5 hours. Acetone (100 ml) and hexane (100 ml) wereadded to the reaction mixture, and the precipitated crystals werecollected by filtration to give N-(2-methoxycarbonylethyl)-2-4-(methylthioimidoyl)benzoylimino!-3-isopropyl-4-methyl-3H-thiazoline-5-carboxamidemethylsulfate (12.7 g).

m.p. 158°˜162° C.

(8) N-(2-Methoxycarbonylethyl)-2-4-(methylthioimidoyl)benzoylimino!-3-isopropyl-4-methyl-3H-thiazoline-5-carboxamidemethylsulfate (3.0 g) was added to a mixture of cyclohexyl4-aminobutyrate methanesulfonate (2.47 g), sodium acetate (529 mg) andmethanol (30 ml) under heating reflux, and the reaction mixture wasfurther heated under reflux for an hour. After evaporation of themethanol under reduced pressure, the residue was dissolved in methylenechloride and washed with water. After evaporation of the solvent,acetone and toluene were added to the residue, and the solvent wasremoved by decantation, followed by drying to giveN-(2-methoxycarbonylethyl)-2-{4-N-(3-cyclohexyloxycarbonylpropyl)amidino!benzoylimino}-3-isopropyl-4-methyl-3H-thiazoline-5-carboxamidemethylsulfate (Compound 13).

m.p. 88°˜90° C.

EXAMPLE 10

Following the reaction procedures similar to those of Examples 1(5) and9(8) using the compound obtained in Example 9(6),N-(2-methoxycarbonylethyl)-2-{4-N-(3-methoxycarbonylpropyl)amidino!benzoylimino}-3-isopropyl-4-methyl-3H-thiazoline-5-carboxamidehydroiodide (Compound 14) was obtained.

m.p. 96°˜98° C.

EXAMPLE 11

N-(2-Methoxycarbonylethyl)-2-4-methylthioimidoyl)benzoylimino!-3-isopropyl-4-methyl-3H-thiazoline-5-carboxamidemethylsulfate (1.0 g) obtained in Example 9(7) was added to a mixture of4-aminobutyric acid (190 mg) and methanol (10 ml) under heating reflux,and the reaction mixture was further heated under reflux for an hour.After evaporation of the methanol under reduced pressure, methanol,acetone and isopropyl ether were added to the residue. The solvent wasremoved by decantation, followed by drying to giveN-(2-methoxycarbonylethyl)-2-{4-N-(3-carboxypropyl)amidino!benzoylimino}-3-isopropyl-4-methyl-3H-thiazoline-5-carboxamidemethylsulfate (Compound 15).

m.p. 73°˜75° C.

EXAMPLE 12

A mixture of Compound 14 (1.0 g), 10% aqueous sodium hydroxide solution(2.4 ml) and methanol (10 ml) was stirred at room temperature for anhour. To the reaction solution were added acetic acid and water, and theprecipitated crystals were collected by filtration to giveN-(2-carboxyethyl)-2-{4-N-(3-carboxypropyl)amidino!benzoylimino}-3-isopropyl-4-methyl-3H-thiazoline-5-carboxamide(Compound 16).

m.p. 160°˜162° C.

EXAMPLE 13

Following the procedure similar to that of Example 7 using Compound 13,N-(2-carboxyethyl)-2-{4-N-(3-cyclohexyloxycarbonylpropyl)amidino!benzoylimino}-3-isopropyl-4-methyl-3H-thiazoline-5-carboxamide(Compound 17) was obtained.

m.p. 170°˜174° C.

EXAMPLE 14

(1) 4-Cyanobenzoyl isothiocyanate (8 g) obtained in Example 9(1) wassuspended in toluene (50 ml), and n-butylamine (4.2 ml) was addedthereto, followed by stirring for 30 minutes. After addition of ethyl2-chloroacetoacetate (14 ml), the mixture was stirred under heatingreflux with removing the water generated in the reaction for 30 minutes.After cooling to room temperature, the precipitated crystals werecollected by filtration to give ethyl3-n-butyl-2-(4-cyanobenzoylimino)-4-methyl-3H-thiazoline-5-carboxylate(8.7 g).

m.p. 186°˜187° C.

(2) A mixture of ethyl3-n-butyl-2-(4-cyanobenzoylimino)-4-methyl-3H-thiazoline-5-carboxylate(8.4 g), 10% aqueous sodium hydroxide solution (36 ml), acetone (100 ml)and methanol (50 ml) was stirred under heating reflux for 6 hours. Aftercooling to room temperature, 3% hydrochloric acid (100 ml) was added,and the precipitated crystals were collected by filtration to give3-n-butyl-2-(4-cyanobenzoylimino)-4-methyl-3H-thiazoline-5-carboxylicacid (8.0 g).

A mixture of3-n-butyl-2-(4-cyanobenzoylimino)-4-methyl-3H-thiazoline-5-carboxylicacid (8 g), WSC.HCl (4.9 g), HOBt.H₂ O (3.9 g), β-alanine methyl esterhydrochloride (3.6 g), triethylamine (3.6 ml) and DMF (100 ml) wasstirred at room temperature for 24 hours. Water (1.2 l) was added to thereaction mixture, and after extraction with methylene chloride, theorganic layer was washed with a saturated aqueous sodium bicarbonatesolution and a saturated aqueous sodium chloride solution and dried overmagnesium sulfate. After concentration under reduced pressure, theprecipitated crude crystals were recrystallized from methanol to giveN-(2-methoxycarbonylethyl)-3-n-butyl-2-(4-cyanobenzoylimino)-4-methyl-3H-thiazoline-5-carboxamide(8.2 g).

m.p. 155.5°˜157.5° C.

(3) A mixture ofN-(2-methoxycarbonylethyl)-3-n-butyl-2-(4-cyanobenzoylimino)-4-methyl-3H-thiazoline-5-carboxamide(8.1 g), sodium hydrosulfide (70%, 3.0 g), magnesium chloridehexahydrate (3.84 g) and DMF (80 ml) was stirred at room temperatureovernight. After addition of water (300 ml), the precipitated crystalswere collected by filtration, and the resulting crude crystals werewashed with 3% hydrochloric acid to giveN-(2-methoxycarbonylethyl)-2-(4-thiocarbamoylbenzoylimino)-3-n-butyl-4-methyl-3H-thiazoline-5-carboxamide(8.8 g).

m.p. 177°˜179.5° C.

(4)N-(2-Methoxycarbonylethyl)-2-(4-thiocarbamoylbenzoylimino)-3-n-butyl-4-methyl-3H-thiazoline-5-carboxamide(8.8 g) was suspended in DMF (50 ml), and then dimethyl sulfate (5.4 ml)was added thereto, followed by stirring at 60° C. for 5 hours. Aftercooling to room temperature, acetone (200 ml) and hexane (150 ml) wereadded to the reaction mixture, and the precipitated crystals werecollected by filtration to give N-(2-methoxycarbonylethyl)-2-4-(methylthioimidoyl)benzoylimino!-3-n-butyl-4-methyl-3H-thiazoline-5-carboxamidemethylsulfate (12.1 g).

m.p. 110°˜113° C.

(5) Following the procedure similar to that of Example 3 usingN-(2-methoxycarbonylethyl)-2-4-(methylthioimidoyl)benzoylimino!-3-n-butyl-4-methyl-3H-thiazoline-5-carboxamidemethylsulfate (1 g), N-(2-methoxycarbonylethyl)-2-{4-N-(3-cyclohexyloxycarbonylpropyl)amidino!benzoylimino}-3-n-butyl-4-methyl-3H-thiazoline-5-carboxamidemethylsulfate (Compound 18) was obtained.

m.p. 70°˜74° C.

EXAMPLE 15

Following the procedure similar to that of Example 7 using Compound 18as a material, N-(2-carboxyethyl)-2-{4-N-(3-cyclohexyloxycarbonylpropyl)amidino!benzoylimino}-3-n-butyl-4-methyl-3H-thiazoline-5-carboxamide(Compound 19) was obtained.

m.p. 204°˜204.5° C. (decomposed)

EXAMPLE 16

A mixture of Compound 18 (0.1 g), 10% aqueous sodium hydroxide solution(0.4 ml) and 2-propanol (4 ml) was stirred at room temperature for 5hours, and adjusted to pH 5 by adding 1% aqueous phosphoric acidsolution. After removal of the solvent by decantation, the oily residuewas crystallized from water--acetone to give N-(2-carboxyethyl)-2-{4-N-(3-carboxypropyl)amidino!benzoylimino}-3-n-butyl-4-methyl-3H-thiazoline-5-carboxamide(Compound 20).

¹ H-NMR (DMSO-d₆) δ (ppm); 0.96 (3H, t, J=7Hz), 1.41 (2H, m), 1.65-1.85(4H, m), 2.10-2.22 (4H, m), 2.61 (3H, s), 3.26-3.45 (4H, m), 4.33 (2H,t, J=7Hz), 7.91 (2H, d, J=8Hz), 8.29 (2H, d, J=8Hz), 8.70 (1H, brs).

EXAMPLE 17

(1) 4-Cyanobenzoyl chloride (12.5 g) was added to a solution of ammoniumthiocyanate (5.8 g) in acetone (125 ml) at room temperature, followed byheating under reflux for 15 minutes. The reaction mixture wasice-cooled, and after removal of the insoluble substance by filtration,the filtrate was evaporated under reduced pressure. To the resultingresidue were added toluene (125 ml) and n-hexylamine (11 ml)successively, followed by stirring for 16 hours. The reaction mixturewas concentrated under reduced pressure, and the residue waschromatographed on silica gel column (ethyl acetate:methylenechloride=4:96) to give 1-(4-cyanobenzoyl)-3-n-hexylthiourea (16 g).

m.p. 95°˜96° C.

(2) A mixture of 1-(4-cyanobenzoyl)-3-n-hexylthiourea (15.5 g), ethyl2-chloroacetoacetate (22 g) and toluene (160 ml) was stirred underheating reflux with removing the water generated in the reaction for 2hours. After cooling to room temperature, the precipitated crystals werecollected by filtration to give ethyl3-n-hexyl-2-(4-cyanobenzoylimino)-4-methyl-3H-thiazoline-5-carboxylate(19.1 g).

m.p. 127°˜128° C.

(3) A mixture of ethyl3-n-hexyl-2-(4-cyanobenzoylimino)-4-methyl-3H-thiazoline-5-carboxylate(18.5 g), 10% aqueous sodium hydroxide solution (37 ml) and acetone (200ml) was stirred under heating reflux for an hour. The reaction mixturewas concentrated under reduced pressure and acidified with 3%hydrochloric acid. The precipitated crystals were collected byfiltration to give3-n-hexyl-2-(4-cyanobenzoylimino)-4-methyl-3H-thiazoline-5-carboxylicacid (17.2 g).

m.p. 216°˜218° C.

(4) A mixture of3-n-hexyl-2-(4-cyanobenzoylimino)-4-methyl-3H-thiazoline-5-carboxylicacid (16.5 g), WSC.HCl (10.2 g), HOBt.H₂ O (10.2 g), β-alanine-t-butylester hydrochloride (9.68 g), triethylamine (7.4 ml) and DMF (180 ml)was stirred at room temperature for 5.5 hours. Water (1.2 l) was addedto the reaction mixture, and after extraction with methylene chloride,the organic layer was washed with a saturated aqueous sodium bicarbonatesolution and a saturated aqueous sodium chloride solution and dried overmagnesium sulfate. After concentration under reduced pressure, theprecipitated crystals were washed with hexane to giveN-(2-t-butoxycarbonylethyl)-3-n-hexyl-2-(4-cyanobenzoylimino)-4-methyl-3H-thiazoline-5-carboxamide(20.5 g).

m.p. 130°˜131° C.

(5) Following the procedure similar to that of Example 14(4) usingN-(2-t-butoxycarbonylethyl)-3-n-hexyl-2-(4-cyanobenzoylimino)-4-methyl-3H-thiazoline-5-carboxamide(20 g),N-(2-t-butoxycarbonylethyl)-2-(4-thiocarbamoylbenzoylimino)-3-n-hexyl-4-methyl-3H-thiazoline-5-carboxamide(21.0 g) was obtained.

m.p. 190°˜190.5° C.

(6)N-(2-t-Butoxycarbonylethyl)-2-(4-thiocarbamoylbenzoylimino)-3-n-hexyl-4-methyl-3H-thiazoline-5-carboxamide(20.5 g) was dissolved in DMF (150 ml), and then dimethyl sulfate (10.9ml) was added thereto. After stirring at room temperature for 24 hours,the reaction mixture was concentrated under reduced pressure andrecrystallized from acetone--hexane to giveN-(2-t-butoxycarbonylethyl)-2-4-(methylthioimidoyl)benzoylimino!-3-n-hexyl-4-methyl-3H-thiazoline-5-carboxamidemethylsulfate (11.5 g).

m.p. 197°˜199° C.

(7) A mixture of N-(2-t-butoxycarbonylethyl)-2-4-(methylthioimidoyl)benzoylimino!-3-n-hexyl-4-methyl-3H-thiazoline-5-carboxamidemethylsulfate (1.5 g), 4-aminobutyric acid (0.2 g) and methanol (15 ml)was stirred under heating reflux for 3 hours. The reaction mixture wasconcentrated under reduced pressure, dissolved in methylene chloride,washed with a saturated aqueous sodium bicarbonate solution and asaturated aqueous sodium chloride solution and dried over magnesiumsulfate. After concentration under reduced pressure, the residue waschromatographed on silica gel column (chloroform:methanol=4:1) to giveN-(2-t-butoxycarbonylethyl)-2-{4-N-(3-carboxypropyl)amidino!benzoylimino}-3-n-hexyl-4-methyl-3H-thiazoline-5-carboxamide(Compound 21).

m.p. 119°˜122° C.

EXAMPLE 18

A mixture of N-(2-t-butoxycarbonylethyl)-2-4-(methylthioimidoyl)benzoylimino!-3-n-hexyl-4-methyl-3H-thiazoline-5-carboxamidemethylsulfate (2 g) obtained in Example 17(6), methyl 4-aminobutyratehydrochloride (0.56 g), sodium acetate (0.3 g) and methanol (20 ml) wasstirred under heating reflux for 3 hours. The reaction mixture wasconcentrated under reduced pressure, dissolved in methylene chloride,washed with a saturated aqueous sodium bicarbonate solution and asaturated aqueous sodium chloride solution and dried over magnesiumsulfate. After concentration under reduced pressure, the residue waschromatographed on silica gel column (chloroform:methanol=9:1) to giveN-(2-t-butoxycarbonylethyl)-2-{4-N-(3-methoxycarbonylpropyl)amidino!benzoylimino}-3-n-hexyl-4-methyl-3H-thiazoline-5-carboxamide(Compound 22).

m.p. 125°˜127° C.

EXAMPLE 19

Following the procedure similar to that of Example 18 using cyclohexyl4-aminobutyrate methanesulfonate as a material,N-(2-t-butoxycarbonylethyl)-2-{4-N-(3-cyclohexyloxycarbonylpropyl)amidino!benzoylimino}-3-n-hexyl-4-methyl-3H-thiazoline-5-carboxamide(Compound 23) was obtained.

m.p. 178°˜181.5° C.

EXAMPLE 20

A mixture of Compound 21 (0.05 g) and trifluoroacetic acid (0.5 ml) wasstirred at room temperature for an hour. The reaction mixture wasconcentrated under reduce pressure, and the residue was crystallizedfrom ether and collected by filtration to give N-(2-carboxyethyl)-2-{4-N-(3-carboxypropyl)amidino!benzoylimino}-3-n-hexyl-4-methyl-3H-thiazoline-5-carboxamidetrifluoroacetate (Compound 24).

m.p. 151°˜153° C.

EXAMPLE 21

Following the reaction procedure similar to that of Example 20, thefollowing compounds were obtained.

N-(2-Carboxyethyl)-2-{4-N-(3-methoxycarbonylpropyl)amidino!benzoylimino}-3-n-hexyl-4-methyl-3H-thiazoline-5-carboxamidetrifluoroacetate (Compound 25)

m.p. 54°˜56° C.

N-(2-Carboxyethyl)-2-{4-N-(3-cyclohexyloxycarbonylpropyl)amidino!benzoylimino}-3-n-hexyl-4-methyl-3H-thiazoline-5-carboxamidetrifluoroacetate (Compound 26)

m.p. 45°˜49° C.

EXAMPLE 22

(1) 4-Cyanobenzoyl chloride (12.5 g) was added to a solution of ammoniumthiocyanate (5.8 g) in acetone (125 ml) at room temperature, followed byheating under reflux for 15 minutes. The reaction mixture wasice-cooled, and after removal of the insoluble substance by filtration,the filtrate was evaporated under reduced pressure. To the resultingresidue were added toluene (125 ml) and n-tetradecylamine (17.7 g)successively, followed by stirring for an hour. The reaction mixture wasconcentrated under reduced pressure, and the residue was chromatographedon silica gel column (ethyl acetate:methylene chloride=2:98) to give1-(4-cyanobenzoyl)-3-n-tetradecylthiourea (21.4 g).

m.p. 78°˜80° C.

(2) A mixture of 1-(4-cyanobenzoyl)-3-n-tetradecylthiourea (21 g), ethyl2-chloroacetoacetate (25 g) and toluene (240 ml) was stirred underheating reflux with removing the water generated in the reaction for 5hours. After cooling to room temperature, the precipitated crystals werecollected by filtration to give ethyl3-n-tetradecyl-2-(4-cyanobenzoylimino)-4-methyl-3H-thiazoline-5-carboxylate(23.4 g).

m.p. 86°˜86.5° C.

(3) A mixture of ethyl3-n-tetradecyl-2-(4-cyanobenzoylimino)-4-methyl-3H-thiazoline-5-carboxylate(23 g), 10% aqueous sodium hydroxide solution (36 ml) and acetone (250ml) was stirred under heating reflux for an hour. The reaction mixturewas concentrated under reduced pressure and acidified with 3%hydrochloric acid. The precipitated crystals were collected byfiltration to give3-n-tetradecyl-2-(4-cyanobenzoylimino)-4-methyl-3H-thiazoline-5-carboxylicacid (21.7 g).

m.p. 176°˜177° C.

(4) A mixture of3-n-tetradecyl-2-(4-cyanobenzoylimino)-4-methyl-3H-thiazoline-5-carboxylicacid (21 g), WSC.HCl (10.0 g), HOBt.H₂ O (10.0 g), β-alanine-t-butylester hydrochloride (9.46 g), triethylamine (7.3 ml) and DMF (200 ml)was stirred at room temperature for 5 hours. Water (1.2 l) was added tothe reaction mixture, and after extraction with methylene chloride, theorganic layer was washed with a saturated aqueous sodium bicarbonatesolution and a saturated aqueous sodium chloride solution and dried overmagnesium sulfate. After concentration under reduced pressure, theresulting crude crystals were washed with hexane to giveN-(2-t-butoxycarbonylethyl)-3-n-tetradecyl-2-(4-cyanobenzoylimino)-4-methyl-3H-thiazoline-5-carboxamide(25.1 g).

m.p. 92.5°˜94° C.

(5) Following the procedure similar to that of Example 14(4) usingN-(2-t-butoxycarbonylethyl)-3-n-tetradecyl-2-(4-cyanobenzoylimino)-4-methyl-3H-thiazoline-5-carboxamide(20 g),N-(2-t-butoxycarbonylethyl)-2-(4-thiocarbamoylbenzoylimino)-3-n-tetradecyl-4-methyl-3H-thiazoline-5-carboxamide(25.5 g) was obtained.

m.p. 150°˜152.5° C.

(6)N-(2-t-Butoxycarbonylethyl)-2-(4-thiocarbamoylbenzoylimino)-3-n-tetradecyl-4-methyl-3H-thiazoline-5-carboxamide(25 g) was dissolved in DMF (150 ml), and then dimethyl sulfate (11 ml)was added thereto. After stirring at room temperature for 5 hours, thereaction mixture was concentrated under reduced pressure to giveN-(2-t-butoxycarbonylethyl)-2-4-(methylthioimidoyl)benzoylimino!-3-n-tetradecyl-4-methyl-3H-thiazoline-5-carboxamidemethylsulfate (32 g).

¹ H-NMR (DMSO-d₆) δ (ppm); 0.85 (3H, t, J=6Hz), 1.0-1.5 (22H, m), 1.42(9H, s), 1.75 (2H, m), 2.48 (2H, t, J=6Hz), 2.62 (3H, s), 2.88 (3H, s),3.40 (3H, s), 3.42 (2H, q, J=6Hz), 4.36 (2H, m), 7.98 (2H, d, J=8Hz),8.34 (1H, t, J=6Hz), 8.39 (2H, d, J=6Hz)

(7) A mixture of N-(2-t-butoxycarbonylethyl)-2-4-(methylthioimidoyl)benzoylimino!-3-n-tetradecyl-4-methyl-3H-thiazoline-5-carboxamidemethylsulfate (2 g), 4-aminobutyric acid (0.32 g) and methanol (20 ml)was stirred under heating reflux for 1.5 hours. The reaction mixture wasconcentrated under reduced pressure, dissolved in methylene chloride,washed with a saturated aqueous sodium bicarbonate solution and asaturated aqueous sodium chloride solution and dried over magnesiumsulfate. After concentration under reduced pressure, the residue waschromatographed on silica gel column (chloroform:methanol=4:1) to giveN-(2-t-butoxycarbonylethyl)-2-{4-N-(3-carboxypropyl)amidino!benzoylimino}-3-n-tetradecyl-4-methyl-3H-thiazoline-5-carboxamide(Compound 27).

m.p. 177°˜179° C.

EXAMPLE 23

A mixture of N-(2-t-butoxycarbonylethyl)-2-4-(methylthioimidoyl)benzoylimino!-3-n-tetradecyl-4-methyl-3H-thiazoline-5-carboxamidemethylsulfate (2 g) obtained in Example 22(6), methyl 4-aminobutyratehydrochloride (0.48 g), sodium acetate (0.3 g) and methanol (20 ml) wasstirred under heating reflux for 3 hours. The reaction mixture wasconcentrated under reduced pressure, dissolved in methylene chloride,washed with a saturated aqueous sodium bicarbonate solution and asaturated aqueous sodium chloride solution and dried over magnesiumsulfate. After concentration under reduced pressure, the residue waschromatographed on silica gel column (chloroform:methanol=9:1) to giveN-(2-t-butoxycarbonylethyl)-2-{4-N-(3-methoxycarbonylpropyl)amidino!benzoylimino}-3-n-tetradecyl-4-methyl-3H-thiazoline-5-carboxamide(Compound 28).

m.p. 81°˜84° C.

EXAMPLE 24

Following the procedure similar to that of Example 23 using cyclohexyl4-aminobutyrate methanesulfonate as a material,N-(2-t-butoxycarbonylethyl)-2-{4-N-(3-cyclohexyloxycarbonylpropyl)amidino!benzoylimino}-3-n-tetradecyl-4-methyl-3H-thiazoline-5-carboxamide(Compound 29) was obtained.

m.p. 97°˜98° C.

EXAMPLE 25

Following the procedure similar to that of Example 20 using each ofCompounds 27, 28 and 29 as materials, the following compounds wereobtained.

N-(2-Carboxyethyl)-2-{4-N-(3-carboxypropyl)amidino!benzoylimino}-3-n-tetradecyl-4-methyl-3H-thiazoline-5-carboxamidetrifluoroacetate (Compound 30)

m.p. 95°˜98° C.

N-(2-Carboxyethyl)-2-{4-N-(3-methoxycarbonylpropyl)amidino!benzoylimino}-3-n-tetradecyl-4-methyl-3H-thiazoline-5-carboxamidetrifluoroacetate (Compound 31)

m.p. 127°˜129° C.

N-(2-Carboxyethyl)-2-{4-N-(3-cyclohexyloxycarbonylpropyl)amidino!benzoylimino}-3-n-tetradecyl-4-methyl-3H-thiazoline-5-carboxamidetrifluoroacetate (Compound 32)

m.p. 130.5°˜131.5° C.

EXAMPLE 26

(1) 4-Cyanobenzoylisothiocyanate (8 g) obtained in Example 9(1) wassuspended in toluene (50 ml), and then benzylamine (4.6 ml) was addedthereto, followed by stirring for 30 minutes. After addition of ethyl2-chloroacetoacetate (14 ml), the mixture was stirred under heatingreflux with removing the water generated in the reaction for 30 minutes.After cooling to room temperature, the precipitated crystals werecollected by filtration to give ethyl3-benzyl-2-(4-cyanobenzoylimino)-4-methyl-3H-thiazoline-5-carboxylate(11 g).

m.p. 189°˜195.5° C.

(2) A mixture of ethyl3-benzyl-2-(4-cyanobenzoylimino)-4-methyl-3H-thiazoline-5-carboxylate(10.8 g), 10% aqueous sodium hydroxide solution (42.5 ml), methylenechloride (150 ml) and methanol (150 ml) was stirred at room temperaturefor 20 minutes, under heating reflux for an hour and then at roomtemperature overnight. The reaction mixture was concentrated underreduced pressure, and the resulting crude crystals were washed withacetone to give sodium3-benzyl-2-(4-cyanobenzoylimino)-4-methyl-3H-thiazoline-5-carboxylate(10.3 g).

A mixture of sodium3-benzyl-2-(4-cyanobenzoylimino)-4-methyl-3H-thiazoline-5-carboxylicacid (10 g), WSC.HCl (5.3 g), HOBt.H₂ O (4.2 g), β-alanine methyl esterhydrochloride (3.9 g) and DMF (100 ml) was stirred at room temperaturefor 24 hours. Water (1.2 l) was added to the reaction mixture, and afterextraction with methylene chloride, the organic layer was washed with 3%hydrochloric acid, a saturated aqueous sodium bicarbonate solution and asaturated aqueous sodium chloride solution and dried over magnesiumsulfate. After concentration under reduced pressure, the resulting crudecrystals were recrystallized from methanol to giveN-(2-methoxycarbonylethyl)-3-benzyl-2-(4-cyanobenzoylimino)-4-methyl-3H-thiazoline-5-carboxamide(8.7 g).

m.p. 191.5°˜194.5° C.

(3) A mixture ofN-(2-methoxycarbonylethyl)-3-benzyl-2-(4-cyanobenzoylimino)-4-methyl-3H-thiazoline-5-carboxamide(8.6 g), sodium hydrosulfide (70%, 3.0 g), magnesium chloridehexahydrate (3.8 g) and DMF (80 ml) was stirred at room temperatureovernight. After addition of water (300 ml), the precipitated crystalswere collected by filtration, and the resulting crude crystals werewashed with 3% hydrochloric acid to giveN-(2-methoxycarbonylethyl)-2-(4-thiocarbamoylbenzoylimino)-3-benzyl-4-methyl-3H-thiazoline-5-carboxamide(9.3 g).

m.p. 187°˜189.5° C.

(4)N-(2-Methoxycarbonylethyl)-2-(4-thiocarbamoylbenzoylimino)-3-benzyl-4-methyl-3H-thiazoline-5-carboxamide(9.2 g) was suspended in DMF (50 ml), and then dimethyl sulfate (5.2 ml)was added thereto, followed by stirring at 60° C. for 4.5 hours. Aftercooling to room temperature, acetone (200 ml) was added, and theprecipitated crystals were collected by filtration to giveN-(2-methoxycarbonylethyl)-2-4-(methylthioimidoyl)benzoylimino!-3-benzyl-4-methyl-3H-thiazoline-5-carboxamidemethylsulfate (9.4 g).

m.p. 187°˜189.5° C.

(5) Following the procedure similar to that of Example 2 usingN-(2-methoxycarbonylethyl)-2-4-(methylthioimidoyl)benzoylimino!-3-benzyl-4-methyl-3H-thiazoline-5-carboxamidemethylsulfate (1 g), N-(2-methoxycarbonylethyl)-2-{4-N-(3-methoxycarbonylpropyl)amidino!benzoylimino}-3-benzyl-4-methyl-3H-thiazoline-5-carboxamidemethylsulfate (0.78 g) (Compound 33) was obtained.

m.p. 116.5°˜118° C.

EXAMPLE 27

Following the procedure similar to that of Example 3 usingN-(2-methoxycarbonylethyl)-2-4-(methylthioimidoyl)benzoylimino!-3-benzyl-4-methyl-3H-thiazoline-5-carboxamidemethylsulfate (1 g) obtained in Example 26(4),N-(2-methoxycarbonylethyl)-2-{4-N-(3-cyclohexyloxycarbonylpropyl)amidino!benzoylimino}-3-benzyl-4-methyl-3H-thiazoline-5-carboxamidemethylsulfate (Compound 34) was obtained.

m.p. 118.5°˜121° C.

EXAMPLE 28

A mixture of Compound 33 (0.5 g), 10% aqueous sodium hydroxide solution(2 ml), water (5 ml) and 2-propanol (20 ml) was stirred at roomtemperature for 5 hours, and adjusted to pH 5 by adding 1% aqueousphosphoric acid solution. After removal of the solvent by decantation,the oily residue was crystallized from water--acetone to giveN-(2-carboxyethyl)-2-{4-N-(3-carboxypropyl)amidino!benzoylimino}-3-benzyl-4-methyl-3H-thiazoline-5-carboxamide(Compound 35).

m.p. 159°˜163° C.

EXAMPLE 29

Following the procedure similar to that of Example 7 using Compound 34as a material, N-(2-carboxyethyl)-2-{4-N-(3-cyclohexyloxycarbonylpropyl)amidino!benzoylimino}-3-benzyl-4-methyl-3H-thiazoline-5-carboxamide(Compound 36) was obtained.

m.p. 191°˜193° C.

EXAMPLE 30

(1) 4-Cyanobenzoyl chloride (12.5 g) was added to a solution of ammoniumthiocyanate (5.8 g) in acetone (125 ml) at room temperature, followed byheating under reflux for 15 minutes. The reaction mixture wasice-cooled, and after removal of the insoluble substance by filtration,the filtrate was evaporated under reduced pressure. To the resultingresidue were added toluene (125 ml) and 2-phenylethylamine (10.4 g)successively, followed by stirring for 2 hours. The reaction mixture wasconcentrated under reduced pressure, and the resulting crude crystalswere washed with ethyl acetate to give1-(4-cyanobenzoyl)-3-(2-phenylethyl)thiourea (14.1 g).

m.p. 142°˜143.5° C.

(2) A mixture of 1-(4-cyanobenzoyl)-3-(2-phenylethyl)thiourea (13.5 g),ethyl 2-chloroacetoacetate (18 g) and toluene (150 ml) was stirred underheating reflux with removing the water generated in the reaction for 4hours. After cooling to room temperature, the precipitated crystals werecollected by filtration to give ethyl3-(2-phenylethyl)-2-(4-cyanobenzoylimino)-4-methyl-3H-thiazoline-5-carboxylate(14.3 g).

m.p. 195.5°˜197.5° C.

(3) A mixture of ethyl3-(2-phenylethyl)-2-(4-cyanobenzoylimino)-4-methyl-3H-thiazoline-5-carboxylate(13.5 g), 10% aqueous sodium hydroxide solution (26 ml) and acetone (150ml) was stirred under heating reflux for 2 hours. The reaction mixturewas concentrated under reduced pressure and acidified with 3%hydrochloric acid. The precipitated crystals were collected byfiltration to give3-(2-phenylethyl)-2-(4-cyanobenzoylimino)-4-methyl-3H-thiazoline-5-carboxylicacid (11.9 g).

m.p. 232°˜233° C.

(4) A mixture of3-(2-phenylethyl)-2-(4-cyanobenzoylimino)-4-methyl-3H-thiazoline-5-carboxylicacid (11.5 g), WSC.HCl (8.5 g), HOBt.H₂ O (6.8 g), β-alanine-t-butylester hydrochloride (6.4 g), triethylamine (4.9 ml) and DMF (200 ml) wasstirred at room temperature for 5 hours. Water (1.2 l) was added to thereaction mixture, and after extraction with methylene chloride, theorganic layer was washed with a saturated aqueous sodium bicarbonatesolution and a saturated aqueous sodium chloride solution and dried overmagnesium sulfate. After concentration under reduced pressure, theresulting crude crystals were recrystallized from ethyl acetate--hexaneto giveN-(2-t-butoxycarbonylethyl)-3-(2-phenylethyl)-2-(4-cyanobenzoylimino)-4-methyl-3H-thiazoline-5-carboxamide(15.9 g).

m.p. 101°˜102° C.

(5) Following the procedure similar to that of Example 14(4) usingN-(2-t-butoxycarbonylethyl)-3-(2-phenylethyl)-2-(4-cyanobenzoylimino)-4-methyl-3H-thiazoline-5-carboxamide(15.5 g),N-(2-t-butoxycarbonylethyl)-2-(4-thiocarbamoylbenzoylimino)-3-(2-phenylethyl)-4-methyl-3H-thiazoline-5-carboxamide(14.1 g) was obtained.

m.p. 220°˜221° C.

(6)N-(2-t-Butoxycarbonylethyl)-2-(4-thiocarbamoylbenzoylimino)-3-(2-phenylethyl)-4-methyl-3H-thiazoline-5-carboxamide(13.5 g) was dissolved in DMF (100 ml), and then dimethyl sulfate (11ml) was added thereto. After stirring at room temperature for 18 hours,the reaction mixture was concentrated under reduced pressure, and theresidue was recrystallized from acetone--hexane to giveN-(2-t-butoxycarbonylethyl)-2-4-(methylthioimidoyl)benzoylimino!-3-(2-phenylethyl)-4-methyl-3H-thiazoline-5-carboxamidemethylsulfate (12.0 g).

m.p. 162.5°˜164.5° C.

(7) A mixture of N-(2-t-butoxycarbonylethyl)-2-4-(methylthioimidoyl)benzoylimino!-3-(2-phenylethyl)-4-methyl-3H-thiazoline-5-carboxamidemethylsulfate (2 g), 4-aminobutyric acid (0.32 g) and methanol (20 ml)was stirred under heating reflux for 2.5 hours. The reaction mixture wasconcentrated under reduced pressure, dissolved in methylene chloride,washed with a saturated aqueous sodium bicarbonate solution and asaturated aqueous sodium chloride solution and dried over magnesiumsulfate. After concentration under reduced pressure, the residue waschromatographed on silica gel column (chloroform:methanol=4:1) to giveN-(2-t-butoxycarbonylethyl)-2-{4-N-(3-carboxypropyl)amidino!benzoylimino}-3-(2-phenylethyl)-4-methyl-3H-thiazoline-5-carboxamide(Compound 37).

m.p. 74°˜77° C.

EXAMPLE 31

A mixture of N-(2-t-butoxycarbonylethyl)-2-4-(methylthioimidoyl)benzoylimino!-3-(2-phenylethyl)-4-methyl-3H-thiazoline-5-carboxamidemethylsulfate (2 g) obtained in Example 30(6), methyl 4-aminobutyratehydrochloride (0.5 g), sodium acetate (0.3 g) and methanol (20 ml) wasstirred under heating reflux for 3 hours. The reaction mixture wasconcentrated under reduced pressure, dissolved in methylene chloride,washed with a saturated aqueous sodium bicarbonate solution and asaturated aqueous sodium chloride solution and dried over magnesiumsulfate. After concentration under reduced pressure, the residue waschromatographed on silica gel column (chloroform:methanol=9:1) to giveN-(2-t-butoxycarbonylethyl)-2-{4-N-(3-methoxycarbonylpropyl)amidino!benzoylimino}-3-(2-phenylethyl)-4-methyl-3H-thiazoline-5-carboxamide(Compound 38).

m.p. 84°˜88° C.

EXAMPLE 32

Following the procedure similar to that of Example 31 using cyclohexyl4-aminobutyrate methanesulfonate as a material,N-(2-t-butoxycarbonylethyl)-2-{4-N-(3-cyclohexyloxycarbonylpropyl)amidino!benzoylimino}-3-(2-phenylethyl)-4-methyl-3H-thiazoline-5-carboxamide(Compound 39) was obtained.

m.p. 42°˜46° C.

EXAMPLE 33

Following the procedure similar to that of Example 20 using each ofCompounds 30 to 32 as materials, the following compounds were obtained.

N-(2-Carboxyethyl)-2-{4-N-(3-carboxypropyl)amidino!benzoylimino}-3-(2-phenylethyl)-4-methyl-3H-thiazoline-5-carboxamidetrifluoroacetate (Compound 40)

m.p. 131°˜134° C.

N-(2-Carboxyethyl)-2-{4-N-(3-methoxycarbonylpropyl)amidino!benzoylimino}-3-(2-phenylethyl)-4-methyl-3H-thiazoline-5-carboxamidetrifluoroacetate (Compound 41)

m.p. 115°˜118° C.

N-(2-Carboxyethyl)-2-{4-N-(3-cyclohexyloxycarbonylpropyl)amidino!benzoylimino}-3-(2-phenylethyl)-4-methyl-3H-thiazoline-5-carboxamidetrifluoroacetate (Compound 42)

m.p. 62°˜65° C.

EXAMPLE 34

(1) 4-Cyanobenzoyl chloride (20 g) was added in portions to a solutionof ammonium thiocyanate (9.2 g) in acetone (200 ml) at room temperature,followed by heating under reflux for 20 minutes. The reaction mixturewas ice-cooled, and after removal of the insoluble substance byfiltration, the filtrate was evaporated under reduced pressure. To theresulting residue were added toluene (100 ml) and cyclopropylamine (7.6g) successively, followed by stirred for 30 minutes. The precipitatedcrystals were collected by filtration and recrystallized from ethylacetate to give 1-(4-cyanobenzoyl)-3-cyclopropylthiourea (20 g) as acolorless powder.

m.p. 151°˜152° C.

(2) A mixture of 1-cyclopropyl-3-(4-cyanobenzoyl)thiourea (19.5 g),ethyl 2-chloroacetoacetate (24.2 ml) and toluene (200 ml) was stirredunder heating reflux with removing the water generated in the reactionfor 2 hours. After cooling to room temperature, the precipitatedcrystals were collected by filtration to give ethyl3-cyclopropyl-2-(4-cyanobenzoylimino)-4-methyl-3H-thiazoline-5-carboxylate(26.7 g).

m.p. 224.5°˜225.5° C.

(3) A mixture of ethyl3-cyclopropyl-2-(4-cyanobenzoylimino)-4-methyl-3H-thiazoline-5-carboxylate(26.3 g), 10% aqueous sodium hydroxide solution (44 ml) and acetone (300ml) was stirred under heating reflux for 2.5 hours. After cooling toroom temperature, the precipitated crystals were collected by filtrationto give sodium3-cyclopropyl-2-(4-cyanobenzoylimino)-4-methyl-3H-thiazoline-5-carboxylate(26.4 g).

m.p. 273°˜274° C. (decomposed)

(4) A mixture of sodium3-cyclopropyl-2-(4-cyanobenzoylimino)-4-methyl-3H-thiazoline-5-carboxylate(26 g), DMC (18.9 g), β-alanine methyl ester hydrochloride (15.6 g),triethylamine (31 ml) and DMF (300 ml) was stirred at room temperaturefor 3 hours. After addition of water (1.2 l), the precipitated crystalswere collected by filtration, and the resulting crude crystals weredissolved in methylene chloride. The insoluble substance was filteredoff using celite, and the mother liquor was concentrated under reducedpressure to giveN-(2-methoxycarbonylethyl)-3-cyclopropyl-2-(4-cyanobenzoylimino)-4-methyl-3H-thiazoline-5-carboxamide(22.7 g).

m.p. 197.5°˜198.5° C.

(5) Following the procedure similar to that of Example 14(4) usingN-(2-methoxycarbonylethyl)-3-cyclopropyl-2-(4-cyanobenzoylimino)-4-methyl-3H-thiazoline-5-carboxamide(22 g),N-(2-methoxycarbonylethyl)-2-(4-thiocarbamoylbenzoylimino)-3-cyclopropyl-4-methyl-3H-thiazoline-5-carboxamide(21.9 g) was obtained.

m.p. 215°˜215.5° C.

(6)N-(2-Methoxycarbonylethyl)-2-(4-thiocarbamoylbenzoylimino)-3-cyclopropyl-4-methyl-3H-thiazoline-5-carboxamide(21 g) was suspended in DMF (150 ml), and after heating to 50° C.,dimethyl sulfate (7.7 ml) was added dropwise over a 5-minute period.After stirring at 55° C. for 2 hours, acetone (500 ml) was added,followed by cooling to room temperature. Hexane (400 ml) was added tothe reaction mixture, and the precipitated crystals were collected byfiltration to give N-(2-methoxycarbonylethyl)-2-4-(methylthioimidoyl)benzoylimino!-3-cyclopropyl-4-methyl-3H-thiazoline-5-carboxamidemethylsulfate (24.5 g).

m.p. 173.5°˜174.5° C. (decomposed)

(7) N-(2-Methoxycarbonylethyl)-2-4-(methylthioimidoyl)benzoylimino!-3-cyclopropyl-4-methyl-3H-thiazoline-5-carboxamidemethylsulfate (3.0 g) was added to a mixture of methyl 4-aminobutyratehydrochloride (1.45 g), sodium acetate (620 mg) and methanol (30 ml)under heating reflux, and the reaction mixture was heated under refluxfor an hour. After evaporation of the methanol under reduced pressure,the residue was dissolved in methylene chloride and washed with water.After evaporation of the solvent, methanol and isopropyl ether wereadded to the residue, and the solvent was separated by decantation. Theresidue was dissolved in methylene chloride again. The solution wasneutralized with a saturated aqueous sodium bicarbonate solution, andevaporated to give N-(2-methoxycarbonylethyl)-2-{4-N-(3-methoxycarbonylpropyl)amidino!benzoylimino}-3-cyclopropyl-4-methyl-3H-thiazoline-5-carboxamide(Compound 43).

m.p. 57°˜58° C.

EXAMPLE 35

Following the procedure similar to that of Example 9(8) usingN-(2-methoxycarbonylethyl)-2-4-(methylthioimidoyl)benzoylimino!-3-cyclopropyl-4-methyl-3H-thiazoline-5-carboxamidemethylsulfate obtained in Example 34(6) and cyclohexyl 4-aminobutyratemethanesulfonate, N-(2-methoxycarbonylethyl)-2-{4-N-(3-cyclohexyloxycarbonylpropyl)amidino!benzoylimino}-3-cyclopropyl-4-methyl-3H-thiazoline-5-carboxamidemethylsulfate (Compound 44) was obtained.

m.p. 82°˜84° C.

EXAMPLE 36

Following the procedure similar to that of Example 4 usingN-(2-methoxycarbonylethyl)-2-4-(methylthioimidoyl)benzoylimino!-3-cyclopropyl-4-methyl-3H-thiazoline-5-carboxamidemethylsulfate obtained in Example 34(6) and4-amino-N-cyclohexylbutyramide hydrochloride,N-(2-methoxycarbonylethyl)-2-{4-N-(3-cyclohexylaminocarbonylpropyl)amidino!benzoylimino}-3-cyclopropyl-4-methyl-3H-thiazoline-5-carboxamidemethylsulfate (Compound 45) was obtained.

¹ H-NMR (DMSO-d₆) δ (ppm); 1.0-1.8 (16H, m), 2.23 (2H, t, J=6Hz), 2.58(2H, t, J=6Hz), 2.67 (3H, s), 3.36 (3H, s), 3.45 (4H, q, J=6Hz), 3.61(3H, s), 7.83 (1H, t, J=6Hz), 7.87 (2H, d, J=8Hz), 8.27 (1H, t, J=6Hz),8.36 (2H, d, J=8Hz), 9.42 (2H, br).

EXAMPLE 37

Following the procedure similar to that of Example 4 usingN-(2-methoxycarbonylethyl)-2-4-(methylthioimidoyl)benzoylimino!-3-cyclopropyl-4-methyl-3H-thiazoline-5-carboxamidemethylsulfate obtained in Example 34(6) and 6-aminocaproanilidehydrochloride, N-(2-methoxycarbonylethyl)-2-{4-N-(5-phenylaminocarbonylpentyl)amidino!benzoylimino}-3-cyclopropyl-4-methyl-3H-thiazoline-5-carboxamidemethylsulfate (Compound 46) was obtained.

¹ H-NMR (DMSO-d₆) δ (ppm); 1.1-1.5 (6H, m), 1.69 (4H, m), 2.35 (2H, t,J=6Hz), 2.58 (2H, t, J=6Hz), 2.66 (3H, s), 3.37 (3H, s), 3.45 (4H, q,J=6Hz), 3.61 (3H, s), 7.01 (1H, t, J=6Hz), 7.28 (2H, t, J=8Hz), 7.61(2H, d, J=8Hz), 7.85 (2H, d, J=8Hz), 8.30 (1H, t, J=6Hz), 8.35 (2H, d,J=8Hz), 9.97 (1H, s).

EXAMPLE 38

Following the procedure similar to that of Example 11 usingN-(2-methoxycarbonylethyl)-2-4-(methylthioimidoyl)benzoylimino!-3-cyclopropyl-4-methyl-3H-thiazoline-5-carboxamidemethylsulfate obtained in Example 34(6),N-(2-methoxycarbonylethyl)-2-{4-N-(3-carboxypropyl)amidino!benzoylimino}-3-cyclopropyl-4-methyl-3H-thiazoline-5-carboxamidemethylsulfate (Compound 47) was obtained.

m.p. 67°˜72° C.

EXAMPLE 39

Following the procedure similar to that of Example 12 using Compound 43,N-(2-carboxyethyl)-2-{4-N-(3-carboxypropyl)amidino!benzoylimino}-3-cyclopropyl-4-methyl-3H-thiazoline-5-carboxamide(Compound 48) was obtained.

m.p. 256°˜256.5° C.

EXAMPLE 40

Following the procedure similar to that of Example 7 using Compound 44,N-(2-carboxyethyl)-2-{4-N-(3-cyclohexyloxycarbonylpropyl)amidino!benzoylimino}-3-cyclopropyl-4-methyl-3H-thiazoline-5-carboxamide(Compound 49) was obtained.

m.p. 199°˜201° C.

EXAMPLE 41

Following the procedure similar to that of Example 8 using Compound 45,N-(2-carboxyethyl)-2-{4-N-(3-cyclohexylaminocarbonylpropyl)amidino!benzoylimino}-3-cyclopropyl-4-methyl-3H-thiazoline-5-carboxamide(Compound 50) was obtained.

m.p. 147°˜149° C.

EXAMPLE 42

Following the procedure similar to that of Example 8 using Compound 46,N-(2-carboxyethyl)-2-{4-N-(5-phenylaminocarbonylpentyl)amidino!benzoylimino}-3-cyclopropyl-4-methyl-3H-thiazoline-5-carboxamide(Compound 51) was obtained.

m.p. 150°˜154° C.

EXAMPLE 43

(1) 4-Cyanobenzoyl chloride (5.8 g) was added in portions to a solutionof ammonium thiocyanate (2.7 g) in acetone (50 ml) at room temperature,followed by heating under reflux for 10 minutes. The reaction mixturewas ice-cooled, and after removal of the insoluble substance byfiltration, the filtrate was evaporated under reduced pressure. To theresulting residue were added toluene (30 ml) and cyclobutylamine (3 ml)successively, followed by stirred for 20 minutes. To the reactionmixture was added ethyl 2-chloroacetoacetate (11.6 ml), followed byheating under reflux with removing the water generated in the reactionfor 100 minutes. The reaction mixture was allowed to stand for cooling,and the precipitated crystals were collected by filtration to give ethyl2-(4-cyanobenzoylimino)-3-cyclobutyl-4-methyl-3H-thiazoline-5-carboxylate.

m.p. 221.5°˜223° C. (decomposed)

(2) A mixture of ethyl2-(4-cyanobenzoylimino)-3-cyclobutyl-4-methyl-3H-thiazoline-5-carboxylate(8 g), 10% aqueous sodium hydroxide solution (13 ml) and acetone (100ml) was stirred under heating reflux for 2 hours. After cooling to roomtemperature, conc. hydrochloric acid (2.8 ml) was added thereto, and theprecipitated crystals were collected by filtration to give2-(4-cyanobenzoylimino)-3-cyclobutyl-4-methyl-3H-thiazoline-5-carboxylicacid (8.6 g).

m.p. 231°˜234° C. (decomposed)

(3) Following the procedure similar to that of Example 36(4) using2-(4-cyanobenzoylimino)-3-cyclobutyl-4-methyl-3H-thiazoline-5-carboxylicacid (8.6 g),N-(2-methoxycarbonylethyl)-2-(4-cyanobenzoylimino)-3-cyclobutyl-4-methyl-3H-thiazoline-5-carboxamidewas obtained.

m.p. 158.5°˜159.5° C.

(4) Following the procedure similar to that of Example 14(4) usingN-(2-methoxycarbonylethyl)-2-(4-cyanobenzoylimino)-3-cyclobutyl-4-methyl-3H-thiazoline-5-carboxamide,N-(2-methoxycarbonylethyl)-2-(4-thiocarbamoylbenzoylimino)-3-cyclobutyl-4-methyl-3H-thiazoline-5-carboxamidewas obtained.

m.p. 196.5°˜197° C. (decomposed)

(5) Following the procedure similar to that of Example 34(6) usingN-(2-methoxycarbonylethyl)-2-(4-thiocarbamoylbenzoylimino)-3-cyclobutyl-4-methyl-3H-thiazoline-5-carboxamideobtained above, N-(2-methoxycarbonylethyl)-2-4-(methylthioimidoyl)benzoylimino!-3-cyclobutyl-4-methyl-3H-thiazoline-5-carboxamidemethylsulfate was obtained.

m.p. 162°˜165° C. (decomposed)

(6) Following the procedure similar to that of Example 34(7) usingN-(2-methoxycarbonylethyl)-2-4-(methylthioimidoyl)benzoylimino!-3-cyclobutyl-4-methyl-3H-thiazoline-5-carboxamidemethylsulfate, N-(2-methoxycarbonylethyl)-2-{4-N-(3-methoxycarbonylpropyl)amidino!benzoylimino}-3-cyclobutyl-4-methyl-3H-thiazoline-5-carboxamide(Compound 52) was obtained.

m.p. 72°˜75° C.

EXAMPLE 44

Following the procedure similar to that of Example 9(8) usingN-(2-methoxycarbonylethyl)-2-4-(methylthioimidoyl)benzoylimino!-3-cyclobutyl-4-methyl-3H-thiazoline-5-carboxamidemethylsulfate obtained in Example 43(5) and cyclohexyl 4-aminobutyratemethanesulfonate, N-(2-methoxycarbonylethyl)-2-{4-N-(3-cyclohexyloxycarbonylpropyl)amidino!benzoylimino}-3-cyclobutyl-4-methyl-3H-thiazoline-5-carboxamidemethylsulfate (Compound 53) was obtained.

m.p. 239°˜240° C.

EXAMPLE 45

Following the procedure similar to that of Example 11 usingN-(2-methoxycarbonylethyl)-2-4-(methylthioimidoyl)benzoylimino!-3-cyclobutyl-4-methyl-3H-thiazoline-5-carboxamidemethylsulfate obtained in Example 43(5),N-(2-methoxycarbonylethyl)-2-{4-N-(3-carboxypropyl)amidino!benzoylimino}-3-cyclobutyl-4-methyl-3H-thiazoline-5-carboxamidemethylsulfate (Compound 54) was obtained.

m.p. 65°˜70° C.

EXAMPLE 46

Following the procedure similar to that of Example 12 using Compound 52,N-(2-carboxyethyl)-2-{4-N-(3-carboxypropyl)amidino!benzoylimino}-3-cyclobutyl-4-methyl-3H-thiazoline-5-carboxamide(Compound 55) was obtained.

m.p. 122°˜124° C.

EXAMPLE 47

Following the procedure similar to that of Example 34(7) using Compound53, N-(2-carboxyethyl)-2-{4-N-(3-cyclohexyloxycarbonylpropyl)amidino!benzoylimino}-3-cyclobutyl-4-methyl-3H-thiazoline-5-carboxamide(Compound 56) was obtained.

m.p. 91°˜93° C.

EXAMPLE 48

(1) Following the reaction procedure similar to that of Example 43(1)using cyclopentylamine in place of cyclobutylamine, ethyl2-(4-cyanobenzoylimino)-3-cyclopentyl-4-methyl-3H-thiazoline-5-carboxylatewas obtained.

m.p. 191.5°˜192° C. (decomposed)

(2) A mixture of ethyl.2-(4-cyanobenzoylimino)-3-cyclopentyl-4-methyl-3H-thiazoline-5-carboxylate(35.5 g), 10% aqueous sodium hydroxide solution (55 ml) and acetone (400ml) was stirred under heating reflux for an hour, and after cooling toroom temperature, conc. hydrochloric acid (3.8 ml) was added thereto. Tothe reaction mixture were added HOBt.H₂ O (17 g), β-alanine methyl esterhydrochloride (15.4 g), WSC.HCl (21.3 g), water (100 ml), DMF (400 ml)and methylene chloride (500 ml) successively, followed by stirring atroom temperature for 5 hours. Water (1 l) was added to the reactionmixture, and the separated organic layer was washed with 3% hydrochloricacid, a saturated aqueous sodium bicarbonate solution and a saturatedaqueous sodium chloride solution. After drying (magnesium sulfate),purification by silica gel column chromatography (methylenechloride--ethyl acetate) gaveN-(2-methoxycarbonylethyl)-3-cyclopentyl-2-(4-cyanobenzoylimino)-4-methyl-3H-thiazoline-5-carboxamide.

m.p. 149.5°˜150.5° C.

(3) Following the procedure similar to that of Example 14(4) usingN-(2-methoxycarbonylethyl)-3-cyclopentyl-2-(4-cyanobenzoylimino)-4-methyl-3H-thiazoline-5-carboxamide,N-(2-methoxycarbonylethyl)-2-4-thiocarbamoylbenzoylimino!-3-cyclopentyl-4-methyl-3H-thiazoline-5-carboxamidewas obtained.

m.p. 149°˜150° C.

(4) Following the procedure similar to that of Example 34(6) usingN-(2-methoxycarbonylethyl)-2-4-thiocarbamoylbenzoylimino!-3-cyclopentyl-4-methyl-3H-thiazoline-5-carboxamide,N-(2-methoxycarbonylethyl)-2-4-(methylthioimidoyl)benzoylimino!-3-cyclopentyl-4-methyl-3H-thiazoline-5-carboxamidemethylsulfate was obtained.

m.p. 186°˜187° C. (decomposed)

(5) Following the procedure similar to that of Example 36(7) usingN-(2-methoxycarbonylethyl)-2-4-(methylthioimidoyl)benzoylimino!-3-cyclopentyl-4-methyl-3H-thiazoline-5-carboxamidemethylsulfate, N-(2-methoxycarbonylethyl)-2-{4-N-(3-methoxycarbonylpropyl)amidino!benzoylimino}-3-cyclopentyl-4-methyl-3H-thiazoline-5-carboxamide(Compound 57) was obtained.

m.p. 65°˜70° C.

EXAMPLE 49

Following the procedure similar to that of Example 9(8) usingN-(2-methoxycarbonylethyl)-2-4-(methylthioimidoyl)benzoylimino!-3-cyclopentyl-4-methyl-3H-thiazoline-5-carboxamidemethylsulfate obtained in Example 48(4) and cyclohexyl 4-aminobutyratemethanesulfonate, N-(2-methoxycarbonylethyl)-2-{4-N-(3-cyclohexyloxycarbonylpropyl)amidino!benzoylimino}-3-cyclobutyl-4-methyl-3H-thiazoline-5-carboxamidemethylsulfate (Compound 58) was obtained.

m.p. 111°˜112° C.

EXAMPLE 50

Following the procedure similar to that of Example 11 usingN-(2-methoxycarbonylethyl)-2-4-(methylthioimidoyl)benzoylimino!-3-cyclopentyl-4-methyl-3H-thiazoline-5-carboxamidemethylsulfate obtained in Example 48(4),N-(2-methoxycarbonylethyl)-2-{4-N-(3-carboxypropyl)amidino!benzoylimino}-3-cyclopentyl-4-methyl-3H-thiazoline-5-carboxamidemethylsulfate (Compound 59) was obtained.

m.p. 122°˜123° C.

EXAMPLE 51

Following the procedure similar to that of Example 12 using Compound 57,N-(2-carboxyethyl)-2-{4-N-(3-carboxypropyl)amidino!benzoylimino}-3-cyclopentyl-4-methyl-3H-thiazoline-5-carboxamide(Compound 60) was obtained.

m.p. 102°˜103° C.

EXAMPLE 52

Following the procedure similar to that of Example 7 using Compound 58,N-(2-carboxyethyl)-2-{4-N-(3-cyclohexyloxycarbonylpropyl)amidino!benzoylimino}-3-cyclopentyl-4-methyl-3H-thiazoline-5-carboxamide(Compound 61) was obtained.

m.p. 200°˜200.5° C.

EXAMPLE 53

(1) Following the reaction procedure similar to that of Example 34(1)using cyclohexylamine in place of cyclopropylamine,1-(4-cyanobenzoyl)-3-cyclohexylthiourea was obtained.

m.p. 136°˜137° C.

(2) Following the reaction procedure similar to that of Example 34(2)using 1-(4-cyanobenzoyl)-3-cyclohexylthiourea, ethyl2-(4-cyanobenzoylimino)-3-cyclohexyl-4-methyl-3H-thiazoline-5-carboxylatewas obtained.

m.p. 232°˜233° C.

(3) A mixture of ethyl2-(4-cyanobenzoylimino)-3-cyclohexyl-4-methyl-3H-thiazoline-5-carboxylate(39.75 g), 10% aqueous sodium hydroxide solution (44 ml), dimethylsulfoxide (398 ml) and methylene chloride (199 ml) was stirred at roomtemperature for an hour, and then the methylene chloride was evaporatedunder reduced pressure, followed by addition of conc. hydrochloric acid(9.2 ml) and water (500 ml). After separation of the solvent bydecantation, and the residue was crystallized with water to give crude2-(4-cyanobenzoylimino)-3-cyclohexyl-4-methyl-3H-thiazoline-5-carboxylicacid, which was then stirred together with HOBt.H₂ O (30.63 g), WSC.HCl(21.09 g), triethylamine (15.33 ml) and DMF (500 ml) at room temperatureovernight. To the reaction mixture was added water (1 l), and theprecipitated crystals were collected by filtration and purified bysilica gel column chromatography (methylene chloride--ethyl acetate) togiveN-(2-methoxycarbonylethyl)-3-cyclohexyl-2-(4-cyanobenzoylimino)-4-methyl-3H-thiazoline-5-carboxamide(40.7 g).

m.p. 194°˜195° C.

(4) Following the procedure similar to that of Example 34(5) usingN-(2-methoxycarbonylethyl)-3-cyclohexyl-2-(4-cyanobenzoylimino)-4-methyl-3H-thiazoline-5-carboxamide,N-(2-methoxycarbonylethyl)-2-4-thiocarbamoylbenzoylimino!-3-cyclohexyl-4-methyl-3H-thiazoline-5-carboxamidewas obtained.

m.p. 228°˜230° C.

(5) A mixture of N-(2-methoxycarbonylethyl)-2-4-thiocarbamoylbenzoylimino!-3-cyclohexyl-4-methyl-3H-thiazoline-5-carboxamide(40 g), methyl iodide (100 ml) and acetone (1 l) was stirred underheating reflux for 2 hours. The reaction mixture was concentrated toabout 500 ml under reduced pressure, and after cooling to roomtemperature, the precipitated crystals were collected by filtration togive N-(2-methoxycarbonylethyl)-2-4-(methylthioimidoyl)benzoylimino!-3-cyclohexyl-4-methyl-3H-thiazoline-5-carboxamidehydroiodide (51.9 g).

m.p. 202.5°˜203.5° C. (decomposed)

(6) Following the procedure similar to that of Example 11 usingN-(2-methoxycarbonylethyl)-2-4-(methylthioimidoyl)benzoylimino!-3-cyclohexyl-4-methyl-3H-thiazoline-5-carboxamidehydroiodide and β-alanine, N-(2-methoxycarbonylethyl)-2-{4-N-(2-carboxyethyl)amidino!benzoylimino}-3-cyclohexyl-4-methyl-3H-thiazoline-5-carboxamidehydroiodide (Compound 62) was obtained.

¹ H-NMR (DMSO-d₆) δ (ppm); 1.3-1.6 (4H, broad), 1.6-2.0 (6H, broad),2.58 (2H, d, J=6Hz), 2.64 (3H, s), 2.93 (2H, broad), 3.44 (2H, q,J=6Hz), 3.60 (2H, broad), 3.62 (3H, s), 4.30 (1H, broad), 7.90 (2H, d,J=8Hz), 8.30 (2H, d, J=8Hz), 8.40 (1H, t, J=6Hz).

EXAMPLE 54

Following the procedure similar to that of Example 11 usingN-(2-methoxycarbonylethyl)-2-4-(methylthioimidoyl)benzoylimino!-3-cyclohexyl-4-methyl-3H-thiazoline-5-carboxamidehydroiodide obtained in Example 53(5), N-(2-methoxycarbonylethyl)-2-{4-N-(3-carboxypropyl)amidino!benzoylimino}-3-cyclohexyl-4-methyl-3H-thiazoline-5-carboxamidehydroiodide (Compound 63) was obtained.

m.p. 57°˜60° C.

EXAMPLE 55

Following the procedure similar to that of Example 11 usingN-(2-methoxycarbonylethyl)-2-4-(methylthioimidoyl)benzoylimino!-3-cyclohexyl-4-methyl-3H-thiazoline-5-carboxamidehydroiodide obtained in Example 53(5) and 4-aminocaproic acid,N-(2-methoxycarbonylethyl)-2-{4-N-(4-carboxypentyl)amidino!benzoylimino}-3-cyclohexyl-4-methyl-3H-thiazoline-5-carboxamidehydroiodide (Compound 64) was obtained.

m.p. 77°˜79° C.

EXAMPLE 56

A mixture of Compound 62 (0.2 g), 10% aqueous sodium hydroxide solution(0.26 ml) and methanol (2 ml) was stirred at 70° C. for 30 minutes.After evaporation of the solvent, 3% hydrochloric acid was added, andthe solvent was separated by decantation, followed by drying to giveN-(2-carboxyethyl)-2-{4-N-(2-carboxyethyl)amidino!benzoylimino}-3-cyclohexyl-4-methyl-3H-thiazoline-5-carboxamide(Compound 65).

m.p. 68°˜70° C.

EXAMPLE 57

Following the procedure similar to that of Example 56 using Compound 63,N-(2-carboxyethyl)-2-{4-N-(3-carboxypropyl)amidino!benzoylimino}-3-cyclohexyl-4-methyl-3H-thiazoline-5-carboxamide(Compound 66) was obtained.

m.p. 183°˜186° C.

EXAMPLE 58

Following the procedure similar to that of Example 56 using Compound 64,N-(2-carboxyethyl)-2-{4-N-(4-carboxypentyl)amidino!benzoylimino}-3-cyclohexyl-4-methyl-3H-thiazoline-5-carboxamide(Compound 67) was obtained.

¹ H-NMR (DMSO-d₆) δ (ppm); 1.3-2.0 (14H, broad), 2.25 (2H, t, J=6Hz),2.50 (2H, t, J=6Hz), 2.63 (3H, s), 2.94 (2H, broad), 3.42 (4H, broad),4.31 (1H, broad), 7.91 (2H, d, 8Hz), 8.31 (2H, d, 8Hz), 8.36 (1H, t,6Hz), 9.20 (1H, broad), 9.55 (1H, broad), 9.88 (1H, t, 6Hz).

We claim:
 1. A thiazoline derivative represented by the formula:##STR11## wherein R¹ is a hydroxyl group, an alkoxy group having 1 to 6carbon atoms, a cycloalkoxy group having 3 to 6 carbon atoms or a grouprepresented by the formula:

    R.sup.4 NH--

wherein R⁴ is a cycloalkyl group having 3 to 6 carbon atoms or a phenylgroup, R² is an alkyl group having 1 to 14 carbon atoms, a cycloalkylgroup having 3 to 6 carbon atoms or a phenylalkyl group having 7 to 10carbon atoms, R³ is a hydrogen atom or an alkyl group having 1 to 6carbon atoms, and n is an integer of 2 to 9 or a pharmaceuticallyacceptable salt thereof.
 2. The thiazoline derivative or thepharmaceutically acceptable salt thereof according to claim 1, whereinR³ is a hydrogen atom.
 3. The thiazoline derivative or thepharmaceutically acceptable salt thereof according to claim 1, whereinR³ is a hydrogen atom and R¹ is a hydroxyl group.
 4. The thiazolinederivative or the pharmaceutically acceptable salt thereof according toclaim 1, wherein R¹ is a hydroxyl group, R³ is a hydrogen atom and R² isa methyl group.
 5. The thiazoline derivative or the pharmaceuticallyacceptable salt thereof according to claim 1, which is selected from thegroup consisting of N-(2-carboxyethyl)-2-{4-N-(3-carboxypropyl)amidino!benzoylimino}-3,4-dimethyl-3H-thiazoline-5-carboxamideand N-(2-carboxyethyl)-2-{4-N-(2-carboxyethyl)amidino!benzoylimino}-3,4-dimethyl-3H-thiazoline-5-carboxamide.